Aza-and polyaza-naphthalenyl-carboxamides useful as HIV integrase inhibitors

ABSTRACT

Aza- and polyaza-naphthalenyl carboxamide derivatives including certain quinoline carboxamide and naphthyridine carboxamide derivatives are described as inhibitors of HIV integrase and inhibitors of HIV replication. These compounds are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, as compounds or pharmaceutically acceptable salts, or as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of preventing, treating or delaying the onset of AIDS and methods of preventing or treating infection by HIV are also described.

This application is the national phase filing under 35 U.S.C. §371 ofInternational Application No. PCT/US 01/31550, filed Oct. 9, 2001, whichclaims benefit of U.S. Provisional Application No. 60/239,708, filedOct. 12, 2000.

FIELD OF THE INVENTION

The present invention is directed to aza- and polyaza-naphthalenylcarboxamides and pharmaceutically acceptable salts thereof, theirsynthesis, and their use as inhibitors of the HIV integrase enzyme. Thecompounds of the present invention include 7-(N-substitutedcarboxamido)-8-hydroxy-1,6-naphthyridines and quinoxalines. Thecompounds and pharmaceutically acceptable salts thereof of the presentinvention are useful for preventing or treating infection by HIV and fortreating AIDS.

References are made throughout this application to various publisheddocuments in order to more fully describe the state of the art to whichthis invention pertains. The disclosures of these references are herebyincorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

A retrovirus designated human immunodeficiency virus (HIV) is theetiological agent of the complex disease that includes progressivedestruction of the immune system (acquired immune deficiency syndrome;AIDS) and degeneration of the central and peripheral nervous system.This virus was previously known as LAV, HTLV-III, or ARV. A commonfeature of retrovirus replication is the insertion by virally-encodedintegrase of proviral DNA into the host cell genome, a required step inHIV replication in human T-lymphoid and monocytoid cells. Integration isbelieved to be mediated by integrase in three steps: assembly of astable nucleoprotein complex with viral DNA sequences; cleavage of twonucleotides from the 3′ termini of the linear proviral DNA; covalentjoining of the recessed 3′ OH termini of the proviral DNA at a staggeredcut made at the host target site. The fourth step in the process, repairsynthesis of the resultant gap, may be accomplished by cellular enzymes.

Nucleotide sequencing of HIV shows the presence of a pol gene in oneopen reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Aminoacid sequence homology provides evidence that the pol sequence encodesreverse transcriptase, integrase and an HIV protease [Toh, H. et al.,EMBO J. 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986);Pearl, L. H. et al., Nature, 329, 351 (1987)]. All three enzymes havebeen shown to be essential for the replication of HIV.

It is known that some antiviral compounds which act as inhibitors of HIVreplication are effective agents in the treatment of AIDS and similardiseases, including reverse transcriptase inhibitors such asazidothymidine (AZT) and efavirenz and protease inhibitors such asindinavir and nelfinavir. The compounds of this invention are inhibitorsof HIV integrase and inhibitors of HIV replication. The inhibition ofintegrase in vitro and HIV replication in cells is a direct result ofinhibiting the strand transfer reaction catalyzed by the recombinantintegrase in vitro in HIV infected cells. The particular advantage ofthe present invention is highly specific inhibition of HIV integrase andHIV replication.

The following references are of interest as background:

Chemical Abstracts No. 33-2525 discloses the preparation of5-chloro-8-hydroxy-1,6-naphthyridine-7-carboxylic acid amide from thecorresponding methyl ester.

Derwent Abstract No. 97-048296 is an abstract of Japanse PublishedApplication No. 08301849. The abstract discloses certain heterocycliccarboxamide derivatives. The derivatives are said to be useful astachykinin receptor inhibitors.N-(3,5-bis(trifluoromethyl)benzyl-1,2-dihydro-N,2-dimethyl-1-oxo-4-pyrrolidino-3-isoquinolinecarboxamide is specifically disclosed.

WO 98/13350 discloses certain quinoline derivatives which inhibitvascular endothelial growth factor. The reference also discloses certain1,8-naphthryidine derivatives; i.e., Examples 53 and 54 respectivelydescribe preparations of2-acetamido-5-(2-fluoro-5-hydroxy-4-methylanilino)-1,8-naphthyridine and2-amino-5-(2-fluoro-5-hydroxy-4-methylanilino)-1,8-naphthyridine.

WO 99/32450 discloses 4-hydroxyquinoline-2-carboxamide derivatives whichare proposed for use in treating herpes virus infections.

WO 98/11073 discloses 8-hydroxyquinoline-7-carboxamides which areproposed for use in treating herpes virus infections.

SUMMARY OF THE INVENTION

The present invention is directed to novel aza- and polyaza-naphthalenylcarboxamides. These compounds are useful in the inhibition of HIVintegrase, the prevention of infection by HIV, the treatment ofinfection by HIV and in the prevention, treatment, and delay in theonset of AIDS and/or ARC, either as compounds, pharmaceuticallyacceptable salts or hydrates (when appropriate), pharmaceuticalcomposition ingredients, whether or not in combination with otherHIV/AIDS antivirals, anti-infectives, immunomodulators, antibiotics orvaccines. More particularly, the present invention includes a compoundof Formula (I):

-   wherein A is a heterocycle;-   A is substituted by R¹, R², R³, and R⁴;-   L is a linker connecting a ring atom of A to the nitrogen of the    —N(R⁵)— moiety, wherein L is    -   (i) a single bond,    -   (ii) —(C₁₋₆ alkyl)-,    -   (iii) —(C₂₋₆ alkenyl)-,    -   (iv) —(C₀₋₆ alkyl)-(C₃₋₆ cycloalkyl)-(C₀₋₆ alkyl)-, or    -   (v) —(C₀₋₆ alkyl)-M-(C₀₋₆ alkyl)-, wherein M is —N(R^(a))—,        —OC(═O)—, or —C(═O)O—; wherein the alkenyl in (iii) and the        alkyls in (ii), (iv), and (v) are independently and optionally        substituted with 1, 2, or 3 substituents independently selected        from the group consisting of halogen, —OH, —C₁₋₆ alkyl, —O—C₁₋₆        alkyl, —CO₂R^(a), —CO₂(CH₂)₁₋₂R^(k), —C₁₋₆ alkyl-OR^(a), —R^(k),        —(CH₂)₁₋₂R^(k), —CH(OR^(a))—R^(k), and —CH(N(R^(a))₂)—R^(k);-   X is N or C—Q¹;-   Y is N or C—Q², provided that X and Y are not both N;-   Z¹ is N or C—Q³;-   Z² is N or C—Q⁴;-   Z³ is N or CH;-   each of Q¹, Q², Q³, and Q⁴ is independently    -   (1) —H.    -   (2) —C₁₋₆ alkyl,    -   (3) —C₁₋₆ haloalkyl,    -   (4) —O—C₁₋₆ alkyl,    -   (5) —O—C₁₋₆ haloalkyl,    -   (6) halo,    -   (7) —CN,    -   (8) —C₁₋₆ alkyl-OR^(a),    -   (9) —C₀₋₆ alkyl-C(═O)R^(a),    -   (10) —C₀₋₆ alkyl-CO₂R^(a),    -   (11) —C₀₋₆ alkyl-SR^(a),    -   (12) —N(R^(a))₂,    -   (13) —C₁₋₆ alkyl-N(R^(a))₂,    -   (14) —C₀₋₆ alkyl-C(═O)N(R^(a))₂,    -   (15) —C₀₋₆ alkyl-G-C₁₋₆ alkyl-C(═O)N(R^(a))₂, wherein G is O, S,        N(R^(a)), or N(SO₂R^(a)),    -   (16) —N(R^(a))—C(R^(a))═O,    -   (17) —C₁₋₆ alkyl-N(R^(a))—C(R^(a))═O,    -   (18) —C(═O)—N(R^(a))—C₁₋₆ alkyl-[C(═O)]₀₋₁—N(R^(a))₂,    -   (19) —C(═O)—N(R^(a))—C₁₋₆ alkyl substituted with 1 or 2-OR^(a),    -   (20) —C₀₋₆ alkyl-SO₂R^(a),    -   (21) —C₀₋₆ alkyl-N(R^(a))SO₂R^(a),    -   (22) —C₂₋₆ alkenyl,    -   (23) —C₂₋₆ alkenyl-C(═O)—N(R^(a))₂,    -   (24) —C₂₋₅ alkynyl,    -   (25) —C₂₋₅ alkynyl-CH₂N(R^(a))₂,    -   (26) —C₂₋₅ alkynyl-CH₂OR^(a),    -   (27) —C₂₋₅ alkynyl-CH₂S(O)_(n)—R^(a), or    -   (28)    -   (29)    -   (30) —C(═NR^(a))—N(R^(a))₂,    -   (31) —N(R^(a))—C₁₋₆ alkyl-S(O)_(n)R^(a),    -   (32) —N(R^(a))—C₁₋₆ alkyl-OR^(a),    -   (33) —N(R^(a))—C₁₋₆ alkyl-N(R^(a))₂,    -   (34) —N(R^(a))—C₁₋₆ alkyl-N(R^(a))—C(R^(a))═O,    -   (35) —N(R^(a))—C₀₋₆ alkyl-[C(═O)]₁₋₂N(R^(a))₂,    -   (36) —N(R^(a))—C₁₋₆ alkyl-CO₂R^(a),    -   (37) —N(R^(a))C(═O)N(R^(a)) —C₁₋₆ alkyl-C(═O)N(R^(a))₂,    -   (38) —N(R^(a))C(═O)—C₁₋₆ alkyl-N(R^(a))₂,    -   (39) —N(R^(a))—SO₂-N(R^(a))₂,    -   (40) —R^(k),    -   (41) —C₁₋₆ alkyl substituted with R^(k),    -   (42) —C₁₋₆ haloalkyl substituted with R^(k),    -   (43) —C₂₋₅ alkenyl-R^(k),    -   (44) —C₂₋₅ alkynyl-R^(k),    -   (45) —C₀₋₆ alkyl-O-R^(k),    -   (46) —C₀₋₆ alkyl-O—C₁₋₆ alkyl-R^(k),    -   (47) —C₀₋₆ alkyl-S(O)_(n)—R^(k),    -   (48) —C₀₋₆ alkyl-S(O)_(n)—C₁₋₆ alkyl-R^(k),    -   (49) —O—C₁₋₆ alkyl-OR^(k),    -   (50) —O—C₁₋₆ alkyl-O—C₁₋₆ alkyl-R^(k),    -   (51) —O—C₁₋₆ alkyl-S(O)_(n)R^(k),    -   (52) —C₀₋₆ alkyl-N(R^(c))—R^(k),    -   (53) —C₀₋₆ alkyl-N(R^(c))—C₁₋₆ alkyl substituted with one or two        R^(k) groups,    -   (54) —C₀₋₆ alkyl-N(R^(c))—C₁₋₆ alkyl-OR^(k),    -   (55) —C₀₋₆ alkyl-C(═O)—R^(k),    -   (56) —C₀₋₆ alkyl-C(═O)N(R^(a))—R^(k),    -   (57) —C₀₋₆ alkyl-N(R^(a))C(═O)—R^(k),    -   (58) —C₀₋₆ alkyl-C(═O)N(R^(a))—C₁₋₆ alkyl-R^(k), or    -   (59) —C₀₋₆ alkyl-N(R^(a))—C₀₋₆ alkyl-S(O)_(n)R^(k);-   each of R¹ and R² is independently:    -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —C₁₋₆ haloalkyl,    -   (4) —O—C₁₋₆ alkyl,    -   (5) —O—C₁₋₆ haloalkyl,    -   (6) —OH    -   (7) halo,    -   (8) —NO₂,    -   (9) —CN,    -   (10) —C₁₋₆ alkyl-OR^(a),    -   (11) —C₀₋₆ alkyl-C(═O)R^(a),    -   (12) —C₀₋₆ alkyl-CO₂R^(a),    -   (13) —C₀₋₆ alkyl-SR^(a),    -   (14) —N(R^(a))₂,    -   (15) —C₁₋₆ alkyl-N(R^(a))₂,    -   (16) —C₀₋₆ alkyl-C(═O)N(R^(a))₂,    -   (17) —C₁₋₆ alkyl-N(R^(a))—C(R^(a))═O,    -   (18) —SO₂R^(a),    -   (19) —N(R^(a))SO₂R^(a),    -   (20) —C₂₋₅ alkenyl,    -   (21) —O—C₁₋₆ alkyl-OR^(a),    -   (22) —O—C₁₋₆ alkyl-SR^(a),    -   (23) —O—C₁₋₆ alkyl-NH—CO₂R^(a),    -   (24) —O—C₂₋₆ alkyl-N(R^(a))₂,    -   (25) —N(R^(a))—C₁₋₆ alkyl-SR^(a),    -   (26) —N(R^(a))—C₁₋₆ alkyl-OR^(a),    -   (27) —N(R^(a))—C₁₋₆ alkyl-N(R^(a))₂,    -   (28) —N(R^(a))—C₁₋₆ alkyl-N(R^(a))—C(R^(a))═O,    -   (29) —R^(k),    -   (30) —C₁₋₆ alkyl substituted with 1 or 2 R^(k) groups,    -   (31) —C₁₋₆ haloalkyl substituted with 1 or 2 R^(k) groups,    -   (32) —C₂₋₅ alkenyl-R^(k),    -   (33) —C₂₋₅ alkynyl-R^(k),    -   (34) —O-R^(k),    -   (35) —O—C₁₋₆ alkyl-R^(k),    -   (36) —S(O)_(n)—R^(k),    -   (37) —S(O)_(n)—C₁₋₆ alkyl-R^(k),    -   (38) —O—C₁₋₆ alkyl-OR^(k),    -   (39) —O—C₁₋₆ alkyl-O—C₁₋₆ alkyl-R^(k),    -   (40) —O—C₁₋₆ alkyl-S(O)_(n)R^(k),    -   (41) —C₁₋₆ alkyl (OR^(b))(R^(k)),    -   (42) —C₁₋₆ alkyl (OR^(b))(—C₁₋₆ alkyl-R^(k)),    -   (43) —C₀₋₆ alkyl-N(R^(b))(R^(k)),    -   (44) —C₀₋₆ alkyl-N(R^(b))(—C₁₋₆ alkyl-R^(k)),    -   (45) —C₁₋₆ alkyl S(O)_(n)—R^(k),    -   (46) —C₁₋₆ alkyl S(O)_(n)—C₁₋₆ alkyl-R^(k),    -   (47) —C₀₋₆ alkyl C(O)—R^(k), or    -   (48) —C₀₋₆ alkyl C(O)—C₁₋₆ alkyl-R^(k),-   each of R³ and R⁴ is independently    -   (1) —H,    -   (2) halo,    -   (3) —CN,    -   (4) —NO₂.    -   (5) —OH,    -   (6) C₁₋₆ alkyl,    -   (7) C₁₋₆ haloalkyl,    -   (8) —O—C₁₋₆ alkyl,    -   (9) —O—C₁₋₆ haloalkyl,    -   (10) —C₁₋₆ alkyl-OR^(a),    -   (11) —C₀₋₆ alkyl-C(═O)R^(a),    -   (12) —C₀₋₆ alkyl-CO₂R^(a),    -   (13) —C₀₋₆ alkyl-SR^(a),    -   (14) —N(R^(a))₂,    -   (15) —C₁₋₆ alkyl-N(R^(a))₂,    -   (16) —C₀₋₆ alkyl-C(═O)N(R^(a))₂,    -   (17) —SO₂R^(a),    -   (18) —N(R^(a))SO₂R^(a),    -   (19) —C₂₋₅ alkenyl,    -   (20) —O—C₁₋₆ alkyl-OR^(a),    -   (21) —O—C₁₋₆ alkyl-SR^(a),    -   (22) —O—C₁₋₆ alkyl-NH—CO₂R^(a),    -   (23) —O—C₂₋₆ alkyl-N(R^(a))₂, or    -   (24) oxo;-   R⁵ is    -   (1) —H,    -   (2) —C₁₋₆ alkyl, optionally substituted with from 1 to 5        substituents independently selected from halogen, —O—C₁₋₆ alkyl,        —O—C₁₋₆ haloalkyl, —N(R^(a))₂, and —CO₂R^(a);    -   (3) aryl optionally substituted with from 1 to 5 substituents        independently selected from halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl,        —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —S—C₁₋₆ alkyl, —CN, and —OH,        or    -   (4) —C₁₋₆ alkyl substituted with R^(k);-   each R^(a) is independently —H, —C₁₋₆ alkyl, or —C₁₋₆ haloalkyl;-   each R^(b) is independently:    -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —C₁₋₄ haloalkyl,    -   (4) —R^(k),    -   (5) —C₂₋₃ alkenyl,    -   (6) —C₁₋₄ alkyl-R^(k),    -   (7) —C₂₋₃ alkenyl-R^(k),    -   (8) —S(O)_(n)—R^(k), or    -   (9) —C(O)—R^(k);-   each R^(c) is independently    -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —C₁₋₆ alkyl substituted with —N(R^(a))₂, or    -   (4) —C₁₋₄ alkyl-aryl, wherein aryl is optionally substituted        with 1 to 5 substituents independently selected from halogen,        C₁₋₆ alkyl, C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl,        —S—C₁₋₆ alkyl, —CN, and —OH;-   each R^(k) is independently carbocycle or heterocycle, wherein the    carbocycle and heterocycle are unsubstituted or substituted with    from 1 to 5 substituents each of which is independently selected    from    -   (a) halogen,    -   (b) —C₁₋₆ alkyl,    -   (c) —C₁₋₆ haloalkyl,    -   (d) —O—C₁₋₆ alkyl,    -   (e) —O—C₁₋₆ haloalkyl,    -   (f) —S—C₁₋₆ alkyl,    -   (g) —CN,    -   (h) —OH,    -   (i) oxo,    -   (j) —C₀₋₆ alkyl-C(═O)N(R^(a))₂,    -   (k) —C₀₋₆ alkyl-C(═O)R^(a),    -   (l) —N(R^(a))—C(═O)R^(a),    -   (m) —N(R^(a))—CO₂R^(a),    -   (n) —C₁₋₆ alkyl-N(R^(a))—C(═O)R^(a),    -   (o) —N(R^(a))₂,    -   (p) —C₁₋₆ alkyl-N(R^(a))₂,    -   (q) —C₁₋₆ alkyl-OR^(a),    -   (r) —C₀₋₆ alkyl-CO₂R^(a),    -   (s) —C₀₋₆ alkyl-O—C₁₋₆ alkyl-OR^(a),    -   (t) —SO₂R^(a),    -   (u) —SO₂N(R^(a))₂,    -   (v) —C₀₋₆ alkyl-CO₂—C₂₋₅ alkenyl,    -   (w) aryl,    -   (x) aryloxy-,    -   (y) —C₁₋₄ alkyl substituted with aryl,    -   (z) heteromonocycle,    -   (aa) —C₁₋₄ alkyl substituted with a heteromonocycle,    -   (bb) heteromonocyclylcarbonyl-C₀₋₆ alkyl-, and    -   (cc) N-heteromonocyclyl-N-C₁₋₆ alkyl-amino-;        -   wherein the aryl group in (w) aryl, (x) aryloxy, and (y)            —C₁₋₄ alkyl substituted with aryl, is optionally substituted            with from 1 to 4 substituents independently selected from            halogen, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, C₁₋₆ alkyl substituted            with N(R^(a))₂, C₁₋₆ haloalkyl, and —OH; and        -   wherein the heteromonocyclyl group in (z) heteromonocycle,            (aa) —C₁₋₄ alkyl substituted with a heteromonocycle, (bb)            heteromonocyclyl-carbonyl-C₀₋₆ alkyl-, and (cc)            N-heteromonocyclyl-N—C₁₋₆ alkyl-amino- is optionally            substituted with from 1 to 4 substituents independently            selected from halogen, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, C₁₋₆            haloalkyl, oxo, and —OH; and-   each n is independently an integer equal to 0, 1 or 2;-   and with the proviso that when Z¹ is C—Q³, Z² is C—Q⁴, Z³ is CH, and    X is C—Q¹, then Y is not C—Q²;-   or a pharmaceutically acceptable salt thereof.

The present invention also includes pharmaceutical compositionscontaining a compound of the present invention and methods of preparingsuch pharmaceutical compositions. The present invention further includesmethods of treating AIDS, methods of delaying the onset of AIDS, methodsof preventing AIDS, methods of preventing infection by HIV, and methodsof treating infection by HIV.

Other embodiments, aspects and features of the present invention areeither further described in or will be apparent from the ensuingdescription, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes the aza- and polyaza-naphthalenylcarboxamides of Formula (I) above. These compounds and pharmaceuticallyacceptable salts thereof are HIV integrase inhibitors.

A first embodiment of the present invention is a compound of Formula I,wherein:

-   each of Q¹, Q², Q³ and Q⁴ is independently    -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —C₁₋₆ fluoroalkyl,    -   (4) —O—C₁₋₆ alkyl,    -   (5) —O—C₁₋₆ fluoroalkyl,    -   (6) halo,    -   (7) —CN,    -   (8) —C₁₋₆ alkyl-OR^(a),    -   (9) —C₀₋₆ alkyl-C(═O)R^(a),    -   (10) —C₀₋₆ alkyl-CO₂R^(a),    -   (11) —C₀₋₆ alkyl-SR^(a),    -   (12) —N(R^(a))₂,    -   (13) —C₁₋₆ alkyl —N(R^(a))₂,    -   (14) —C₀₋₆ alkyl-C(═O)N(R^(a))₂,    -   (15) —C₁₋₆ alkyl-N(R^(a))—C(R^(a))═O,    -   (16) —SO₂R^(a),    -   (17) —N(R^(a))SO₂R^(a),    -   (18) —C₂₋₅ alkynyl, (19) —C₂₋₅ alkynyl-CH₂N(R^(a))₂,    -   (20) —C₂₋₅ alkynyl-CH₂OR^(a),    -   (21)    -   (22) —N(R^(a))—C₁₋₆ alkyl-SR^(a),    -   (23) —N(R^(a))—C₁₋₆ alkyl-OR^(a),    -   (24) —N(R^(a))—C₁₋₆ alkyl-N(R^(a))₂,    -   (25) —N(R^(a))—C₁₋₆ alkyl-N(R^(a))—C(R^(a))═O,    -   (26) —R^(k),    -   (27) —C₁₋₆ alkyl substituted with R^(k),    -   (28) —C₁₋₆ fluoroalkyl substituted with R^(k),    -   (29) —C₂₋₅ alkenyl-R^(k),    -   (30) —C₂₋₅ alkynyl-R^(k),    -   (31) —O-R^(k),    -   (32) —O—C₁₋₁₄ alkyl-R^(k),    -   (33) —S(O)_(n)—R^(k),    -   (34) —S(O)_(n)—C₁₋₄ alkyl-R^(k),    -   (35) —O—C₁₋₆ alkyl-OR^(k),    -   (36) —O—C₁₋₆ alkyl-O—C₁₋₄ alkyl-R^(k),    -   (37) —O—C₁₋₆ alkyl-SR^(k),    -   (38) —N(R^(c))—R^(k),    -   (39) —N(R^(c))—C₁₋₆ alkyl substituted with one or two R^(k)        groups,    -   (40) —N(R^(c))—C₁₋₆ alkyl-OR^(k),    -   (41) —C(═O)N—C₁₋₆ alkyl-R^(k),    -   (42) —C₂₋₅ alkynyl-CH₂S(O)_(n)—R^(a), or    -   (43) —C(═NR^(a))—N(R^(a))₂;-   each of R¹ and R² is independently:    -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —C₁₋₆ fluoroalkyl,    -   (4) —O—C₁₋₆ alkyl,    -   (5) —O—C₁₋₆ fluoroalkyl,    -   (6) —OH    -   (7) halo,    -   (8) —NO₂,    -   (9) —CN,    -   (10) —C₁₋₆ alkyl-OR^(a),    -   (11) —C₀₋₆ alkyl-C(═O)R^(a),    -   (12) —C₀₋₆ alkylCO₂R^(a),    -   (13) —C₀₋₆ alkyl-SR^(a),    -   (14) —N(R^(a))₂,    -   (15) —C₁₋₆ alkyl N(R^(a))₂,    -   (16) —C₀₋₆ alkyl-C(═O)N(R^(a))₂,    -   (17) —C₁₋₆ alkyl-N(R^(a))—C(R^(a))═O,    -   (18) —SO₂R^(a),    -   (19) —N(R^(a))SO₂R^(a),    -   (20) —C₂₋₅ alkenyl,    -   (21) —O—C₁₋₆ alkyl-OR^(a),    -   (22) —O—C₁₋₆ alkyl-SR^(a),    -   (23) —O—C₁₋₆ alkyl-NH—CO₂R^(a),    -   (24) —O—C₂₋₆ alkyl-N(R^(a))₂,    -   (25) —N(R^(a))—C₁₋₆ alkyl-SR^(a),    -   (26) —N(R^(a))—C₁₋₆ alkyl-OR^(a),    -   (27) —N(R^(a))—C₁₋₆ alkyl-N(R^(a))₂,    -   (28) —N(R^(a))—C₁₋₆ alkyl-N(R^(a))—C(R^(a))═O,    -   (29) —R^(k),    -   (30) —C₁₋₆ alkyl substituted with 1 or 2 R^(k) groups,    -   (31) —C₁₋₆ fluoroalkyl substituted with 1 or 2 R^(k) groups,    -   (32) —C₂₋₅ alkenyl-R^(k),    -   (33) —C₂₋₅ alkynyl-R^(k),    -   (34) —OR^(k),    -   (35) —O—C₁₋₄ alkyl-R^(k),    -   (36) —S(O)_(n)—R^(k),    -   (37) —S(O)_(n)—C₁₋₄ alkyl-R^(k),    -   (38) —O—C₁₋₆ alkyl-OR^(k),    -   (39) —O—C₁₋₆ alkyl-O—C₁₋₄ alkyl-R^(k),    -   (40) —O—C₁₋₆ alkyl-SR^(k),    -   (41) —C₁₋₆ alkyl (OR^(b))(R^(k)),    -   (42) —C₁₋₆ alkyl (OR^(b))(—C₁₋₄ alkyl-R^(k)),    -   (43) —C₀₋₆ alkyl-N(R^(b))(R^(k)),    -   (44) —C₀₋₆ alkyl-N(R^(b))(—C₁₋₄ alkyl-R^(k)),    -   (45) —C₁₋₆ alkyl S(O)_(n)—R^(k),    -   (46) —C₁₋₆ alkyl S(O)_(n)—C₁₋₄ alkyl-R^(k),    -   (47) —C₀₋₆ alkyl C(O)—R^(k), or    -   (48) —C₀₋₆ alkyl C(O)—C₁₋₄ alkyl-R^(k),-   each of R³ and R⁴ is independently    -   (1) —H,    -   (2) halo,    -   (3) —CN,    -   (4) —NO₂,    -   (5) —OH,    -   (6) C₁₋₆ alkyl,    -   (7) C₁₋₆ fluoroalkyl,    -   (8) —O—C₁₋₆ alkyl,    -   (9) —O—C₁₋₆ fluoroalkyl,    -   (10) —C₁₋₆ alkyl-OR^(a),    -   (11) —C₀₋₆ alkyl-C(═O)R^(a),    -   (12) —C₀₋₆ alkyl-CO₂R^(a),    -   (13) —C₀₋₆ alkyl-SR^(a),    -   (14) —N(R^(a))₂,    -   (15) —C₁₋₆ alkyl N(R^(a))₂,    -   (16) —C₀₋₆ alkyl-C(═O)N(R^(a))₂,    -   (17) —SO₂R^(a),    -   (18) —N(R^(a))SO₉R^(a),    -   (19) —C₂₋₅ alkenyl,    -   (20) —O—C₁₋₆ alkyl-OR^(a),    -   (21) —O—C₁₋₆ alkyl-SR^(a),    -   (22) —O—C₁₋₆ alkyl-NH—CO₂R^(a),    -   (23) —O—C₂₋₆ alkyl-N(R^(a))₂, or    -   (24) oxo;-   R⁵ is    -   (1) —H,    -   (2) —C₁₋₆ alkyl, optionally substituted with from 1 to 3        substituents independently selected from halogen, —O—C₁₋₆ alkyl,        —O—C₁₋₆ fluoroalkyl, —N(R^(a))₂, and —CO₂R^(a);    -   (3) aryl optionally substituted with from 1 to 5 substituents        independently selected from halogen, C₁₋₆ alkyl, C₁₋₆        fluoroalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ fluoroalkyl, —S—C₁₋₆ alkyl,        —CN, and —OH, or    -   (4) —C₁₋₆ alkyl substituted with R^(k);-   each R^(a) is independently —H, —C₁₋₆ alkyl, or —C₁₋₆ fluoroalkyl;-   each R^(b) is independently:    -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —C₁₋₄ fluoroalkyl,    -   (4) —R^(k),    -   (5) —C₂₋₃ alkenyl,    -   (6) —C₁₋₄ alkyl-R^(k),    -   (7) —C₂₋₃ alkenyl-R^(k),    -   (8) —S(O)_(n)—R^(k), or    -   (9) —C(O)—R^(k);-   each R^(c) is independently    -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —C₁₋₆ alkyl substituted with —N(R^(a))₂, or    -   (4) —C₁₋₄ alkyl-aryl, wherein aryl is optionally substituted        with 1 to 5 substituents independently selected from halogen,        C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆        fluoroalkyl, —S—C₁₋₆ alkyl, —CN, and —OH;-   each R^(k) is independently carbocycle or heterocycle, wherein the    carbocycle and heterocycle are unsubstituted or substituted with    from 1 to 5 substituents each of which is independently selected    from    -   (a) halogen,    -   (b) C₁₋₆ alkyl,    -   (c) C₁₋₆ fluoroalkyl,    -   (d) —O—C₁₋₆ alkyl,    -   (e) —O—C₁₋₆ fluoroalkyl,    -   (f) —S—C₁₋₆ alkyl,    -   (g) —CN,    -   (h) —OH,    -   (i) oxo,    -   (j) —(CH₂)₀₋₃C(═O)N(R^(a))₂,    -   (k) —(CH₂)₀₋₃C(═O)R^(a),    -   (l) —N(R^(a))—C(═O)R^(a),    -   (m) —N(R^(a))—C(═O)OR^(a),    -   (n) —(CH₂)₁₋₃N(R^(a))—C(═O)R^(a),    -   (o) —N(R^(a))₂,    -   (p) —C₁₋₆ alkyl-N(R^(a))₂,    -   (q) aryl,    -   (r) aryloxy-,    -   (s) —C₁₋₄ alkyl substituted with aryl,    -   (t) heteromonocycle,    -   (u) —C₁₋₄ alkyl substituted with a heteromonocycle,    -   (v) heteromonocyclylcarbonyl-C₀₋₆ alkyl-, and    -   (w) N-heteromonocyclyl-N—C₁₋₆ alkyl-amino-;        -   wherein the aryl group in (q) aryl, (r) aryloxy, and (s)            —C₁₋₄ alkyl substituted with aryl, is optionally substituted            with from 1 to 3 substituents independently selected from            halogen, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, C₁₋₆ alkyl substituted            with N(R^(a))₂, C₁₋₆ fluoroalkyl, and —OH; and        -   wherein the heteromonocyclyl group in (t) heteromonocycle,    -   (u) —C₁₋₄ alkyl substituted with a heteromonocycle,    -   (v) heteromonocyclyl-carbonyl-C₀₋₆ alkyl-, and (x)        N-heteromonocyclyl-N—C₁₋₆ alkyl-amino- is optionally substituted        with from 1 to 3 substituents independently selected from        halogen, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, oxo, and        —OH; and-   and all other variables are as originally defined above;-   and with the proviso that when Z¹ is C—Q³, Z² is C—Q⁴, Z³ is CH, and    X is C—Q¹, then Y is not C—Q²;-   or a pharmaceutically acceptable salt thereof.

A second embodiment of the present invention is a compound of Formula(I), wherein

-   A is    -   (i) a 4- to 7-membered saturated or unsaturated monocylic        heterocycle which contains from 1 to 4 nitrogen atoms, from zero        to 2 heteroatoms selected from oxygen and sulfur, and a balance        of carbon atoms, with at least one of the ring atoms being        carbon;    -   (ii) a 7- to 11-membered fused bicyclic heterocycle either ring        of which is saturated or unsaturated, wherein the fused bicyclic        heterocycle contains from 1 to 6 heteroatoms selected from        nitrogen, oxygen and sulfur, and a balance of carbon atoms with        at least two of the ring atoms being carbon; or    -   (iii) a 11- to 15-membered fused tricyclic heterocycle any ring        of which is saturated or unsaturated, wherein the fused        tricyclic heterocycle contains from 1 to 6 nitrogen atoms, from        zero to 3 heteroatoms selected from oxygen and sulfur, and a        balance of carbon atoms with at least three of the ring atoms        being carbon;-   L is    -   (i) a single bond;    -   (ii) —(CH₂)₁₋₅—, which is optionally substituted with 1 or 2        substituents independently selected from the group consisting of        halogen, —OH, —C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —CO₂R^(a),        —CO₂(CH₂)₁₋₂R^(k), —C₁₋₆ alkyl-OR^(a), —R^(k), —(CH₂)₁₋₂R^(k),        —CH(OR^(a))—R^(k), and —CH(N(R^(a))₂)—R^(k);    -   (iii) —(CH₂)₀₋₂—CH═CH—(CH₂)₁₋₂—, which is optionally substituted        with 1 or 2 substituents independently selected from the group        consisting of halogen, —OH, —C₁₋₆ alkyl, and —O—C₁₋₆ alkyl; or    -   (iv)    -    wherein u and v are each integers having a value of from 0 to        4, provided that the sum of u+v is 1, 2, 3 or 4;-   R⁵ is    -   (1) —H,    -   (2) —C₁₋₄ alkyl, optionally substituted with from 1 to 3        substituents independently selected from halogen, —O—C₁₋₆ alkyl,        —O—C₁₋₆ fluoroalkyl, —N(R^(a))₂, and —CO₂R^(a);    -   (3) phenyl optionally substituted with from 1 to 5 substituents        independently selected from halogen, C₁₋₆ alkyl, C₁₋₆        fluoroalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ fluoroalkyl, —S—C₁₋₆ alkyl,        —CN, and —OH, or    -   (4) —C₁₋₄ alkyl substituted with R^(k);-   each R^(a) is independently —H or —C₁₋₆ alkyl;-   each R^(c) is independently    -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —C₁₋₄ alkyl substituted with —N(R^(a))₂, or    -   (4) —C₁₋₄ alkyl-phenyl, wherein the phenyl is optionally        substituted with 1 to 5 substituents independently selected from        halogen, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆        fluoroalkyl, —S—C₁₋₆ alkyl, —CN, and —OH;-   each R^(k) is independently:    -   (1) aryl selected from phenyl and naphthyl, wherein aryl is        unsubstituted or substituted with from 1 to 5 substituents        independently selected from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) C₁₋₆ fluoroalkyl,        -   (d) —O—C₁₋₆ alkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) phenyl,        -   (g) —S—C₁₋₆ alkyl,        -   (h) —CN,        -   (i) —OH,        -   (j) phenyloxy, unsubstituted or substituted with from 1 to 3            substituents independently selected from:            -   (i) halogen,            -   (ii) C₁₋₆ alkyl,            -   (iii) C₁₋₆ fluoroalkyl, and            -   (iv) —OH,        -   (k) —N(R^(a))₂,        -   (I) —C₁₋₆ alkyl-N(R^(a))₂,        -   (m) —R^(t),        -   (p) —(CH₂)₀₋₃C(═O)N(R^(a))₂, and        -   (q) —(CH₂)₀₋₃C(═O)R^(a);    -   (2) —C₃₋₇ cycloalkyl, unsubstituted or substituted with from 1        to 3 substituents independently selected from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) —O—C₁₋₆ alkyl,        -   (d) C₁₋₆ fluoroalkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) —CN,        -   (h) phenyl, and        -   (j) —OH;    -   (3) —C₃₋₇ cycloalkyl fused with a phenyl ring, unsubstituted or        substituted with from 1 to 5 substituents independently selected        from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) —O—C₁₋₆ alkyl,        -   (d) C₁₋₆ fluoroalkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) —CN, and        -   (g) —OH;    -   (4) a 5- or 6-membered heteroaromatic ring containing from 1 to        4 heteroatoms independently selected from oxygen, nitrogen and        sulfur, wherein the heteroaromatic ring is unsubstituted or        substituted on nitrogen or carbon with from 1 to 5 substituents        independently selected from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) C₁₋₆ fluoroalkyl,        -   (d) —O—C₁₋₆ alkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) phenyl,        -   (g) —S—C₁₋₆ alkyl,        -   (h) —CN,        -   (i) —OH,        -   (j) phenyloxy, unsubstituted or substituted with from 1 to 3            substituents independently selected from:            -   (i) halogen,            -   (ii) C₁₋₆ alkyl,            -   (iii) C₁₋₆ fluoroalkyl, and            -   (iv) —OH,        -   (k) —N(R^(a))₂,        -   (l) —C₁₋₆ alkyl-N(R^(a))₂,        -   (m) —R^(t),        -   (n) oxo,        -   (o)—(CH₂)₀₋₃C(═O)N(R^(a))₂, and        -   (p) —(CH₂)₀₋₃C(═O)R^(a);    -   (5) a 5- or 6-membered saturated heterocyclic ring containing 1        or 2 heteroatoms independently selected from oxygen, nitrogen        and sulfur, wherein the heterocyclic ring is unsubstituted or        substituted with from 1 to 4 substituents independently selected        from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) —O—C₁₋₆ alkyl,        -   (d) C₁₋₆ fluoroalkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) —CN,        -   (g) oxo,        -   (h) phenyl        -   (i) benzyl,        -   (j) phenylethyl,        -   (k) —OH,        -   (l) —(CH₂)₀₋₃C(═O)N(R^(a))₂,        -   (m) —(CH₂)₀₋₃C(═O)R^(a),        -   (n) —N(R^(a))—C(═O)R^(a),        -   (o) —N(R^(a))—C(═O)OR^(a),        -   (p) —(CH₂)₁₋₃N(R^(a))—C(═O)R^(a),        -   (q) —N(R^(a))₂,        -   (r) —(CH₂)₁₋₃N(R^(a))₂,        -   (s) —(CH₂)₀₋₃C(═O)R^(t),        -   (t) —R^(t),        -   (u) —N(R^(a))R^(t), and        -   (v) —(CH₂)₁₋₃R^(t); or    -   (6) an 8- to 10-membered heterobicyclic ring containing from 1        to 4 heteroatoms independently selected from oxygen, nitrogen        and sulfur, wherein the heterobicyclic ring is saturated or        unsaturated, and is unsubstituted or substituted with from 1 to        5 substituents independently selected from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) —O—C₁₋₆ alkyl,        -   (d) C₁₋₆ fluoroalkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) —CN,        -   (g) ═O, and        -   (h) —OH; and-   R^(t) is naphthyl or a 5- or 6-membered heteromonocylic ring    containing from 1 to 4 nitrogen atoms, wherein the heteromonocyclic    ring is saturated or unsaturated, and wherein the naphthyl or the    heteromonocyclic ring is unsubstituted or substituted with 1 or 2    substituents independently selected from halogen, oxo, C₁₋₄ alkyl,    and —O—C₁₋₄ alkyl;-   and all other variables are as defined in the first embodiment;-   and with the proviso that when Z¹ is C—Q³, Z² is C—Q⁴, Z³ is CH, and    X is C—Q¹, then Y is not C—Q²;-   or a pharmaceutically acceptable salt thereof.

A third embodiment of the present invention is a compound of Formula I,wherein each R^(k) is independently:

-   -   (1) aryl selected from phenyl and naphthyl, wherein aryl is        unsubstituted or substituted with from 1 to 4 substituents        independently selected from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) C₁₋₆ fluoroalkyl,        -   (d) —O—C₁₋₆ alkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) phenyl,        -   (g) —S—C₁₋₆ alkyl,        -   (h) —CN,        -   (i) —OH,        -   (j) phenyloxy, unsubstituted or substituted with from 1 to 3            substituents independently selected from:            -   (i) halogen,            -   (ii) C₁₋₆ alkyl,            -   (iii) C₁₋₆ fluoroalkyl, and            -   (iv) —OH,        -   (k) —N(R^(a))₂,        -   (l) —C₁₋₆ alkyl-N(R^(a))₂,        -   (m) —R^(t),        -   (p) —(CH₂)₀₋₃C(═O)N(R^(a))₂, and        -   (q) —(CH₂)₀₋₃C(═O)R^(a);    -   (2) —C₃₋₆ cycloalkyl, unsubstituted or substituted with from 1        to 3 substituents independently selected from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) —O—C₁₋₆ alkyl,        -   (d) C₁₋₆ fluoroalkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) —CN,        -   (h) phenyl, and        -   (j) —OH;    -   (3) —C₃₋₆ cycloalkyl fused with a phenyl ring, unsubstituted or        substituted with from 1 to 4 substituents independently selected        from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) —O—C₁₋₆ alkyl,        -   (d) C₁₋₆ fluoroalkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) —CN, and        -   (g) —OH;    -   (4) a 5- or 6-membered heteroaromatic ring selected from        thienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolyl,        isothiazolyl, oxazolyl, isooxazolyl, pyrazinyl, pyrimidinyl,        triazolyl, tetrazolyl, furanyl, and pyridazinyl, wherein the        heteroaromatic ring is unsubstituted or substituted on nitrogen        or carbon with from 1 to 4 substituents independently selected        from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) C₁₋₆ fluoroalkyl,        -   (d) —O—C₁₋₆ alkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) phenyl,        -   (g) —S—C₁₋₆ alkyl,        -   (h) —CN,        -   (i) —OH,        -   (j) phenyloxy, unsubstituted or substituted with from 1 to 3            substituents independently selected from:            -   (i) halogen,            -   (ii) C₁₋₆ alkyl,            -   (iii) C₁₋₆ fluoroalkyl, and            -   (iv) —OH,        -   (k) —N(R^(a))₂,        -   (l) —C₁₋₆ alkyl-N(R^(a))₂,        -   (m) —R^(t),        -   (n) oxo,        -   (o)—(CH₂)₀₋₃C(═O)N(R^(a))₂, and        -   (p) —(CH₂)₀₋₃C(═O)R^(a);    -   (5) a 5- or 6-membered saturated heterocyclic ring selected from        piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,        oxazolidinyl, isooxazolidinyl, isothiazolidinyl, pyrrolidinyl,        imidazolidinyl, piperazinyl, tetrahydrofuranyl, and        pyrazolidinyl, wherein the heterocyclic ring is unsubstituted or        substituted with from 1 to 3 substituents independently selected        from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) —O—C₁₋₆ alkyl,        -   (d) C₁₋₆ fluoroalkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) —CN,        -   (g) ═O,        -   (h) phenyl        -   (i) benzyl,        -   (j) phenylethyl,        -   (k) —OH,        -   (l) —(CH₂)₀₋₃C(═O)N(R^(a))₂,        -   (m) —(CH₂)₀₋₃C(═O)R^(a),        -   (n) N(R^(a))—C(═O)R^(a),        -   (o) N(R^(a))—C(═O)OR^(a),        -   (p) (CH₂)₁₋₃N(R^(a))—C(═O)R^(a),        -   (q) N(R^(a))₂,        -   (r) (CH₂)₁₋₃N(R^(a))₂,        -   (s) —(CH₂)₀₋₃C(═O)R^(t),        -   (t) —R^(t),        -   (u) —N(R^(a))R^(t), and        -   (v) —(CH₂)₁₋₃R^(t); or    -   (6) an 8- to 10-membered heterobicyclic ring selected from        indolyl, benzotriazolyl, benzoimidazolyl,        imidazo[4,5-b]pyridinyl, dihydroimidazo[4,5-b]pyridinyl,        pyrazolo[4,3-c]pyridinyl, dihydropyrazolo[4,3c]pyridinyl,        tetrahydropyrazolo[4,3-c]pyridinyl, pyrrolo[1,2-a]pyrazinyl,        dihydropyrrolo[1,2-a]pyrazinyl,        tetrahydropyrrolo[1,2-a]pyrazinyl,        octahydropyrrolo[1,2-a]pyrazinyl, isoindolyl, indazolyl,        indolinyl, isoindolinyl, quinolinyl, isoquinolinyl,        quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, and        isochromanyl, wherein the bicyclic ring is unsubstituted or        substituted with 1 or 2 substituents independently selected        from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) —O—C₁₋₆ alkyl,        -   (d) C₁₋₆ fluoroalkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) —CN,        -   (g) ═O, and        -   (h) —OH; and            R^(t) is naphthyl or a 5- or 6-membered heteromonocylic ring            selected from pyrrolidinyl, pyrazolidinyl, imidazolinyl,            piperidinyl, piperazinyl, pyrrolyl, pyridyl, imidazolyl,            pyrazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl,            and pyradizinyl; and wherein the naphthyl or the            heteromonocyclic ring is unsubstituted or substituted with 1            or 2 substituents independently selected from halogen, oxo,            C₁₋₄ alkyl, and —O—C₁₋₄ alkyl;            and all other variables are as defined in the second            embodiment            and with the proviso that when Z¹ is C—Q³, Z² is C—Q⁴, Z³ is            CH, and X is C—Q¹, then Y is not C—Q²;            or a pharmaceutically acceptable salt thereof.

A fourth embodiment of the present invention is a compound of Formula I,wherein:

-   A is    -   (i) a 5- or 6-membered saturated or unsaturated monocylic        heterocycle which contains from 1 to 4 nitrogen atoms, from zero        to 2 heteroatoms selected from oxygen and sulfur, and a balance        of carbon atoms, with at least one of the ring atoms being        carbon;    -   (ii) a 8- to 11-membered fused bicyclic heterocycle either ring        of which is saturated or unsaturated, wherein the fused bicyclic        heterocycle contains from 1 to 5 nitrogen atoms, from zero to 3        heteroatoms selected from oxygen and sulfur, and a balance of        carbon atoms with at least two of the ring atoms being carbon;        or    -   (iii) a 12- to 14-membered fused tricyclic heterocycle any ring        of which is saturated or unsaturated, wherein the fused        tricyclic heterocycle contains from 1 to 6 nitrogen atoms, from        zero to 3 heteroatoms selected from oxygen and sulfur, and a        balance of carbon atoms with at least three of the ring atoms        being carbon;-   and all other variables are as defined in the second embodiment;-   and with the proviso that when Z¹ is C—Q³, Z² is C—Q⁴, Z³ is CH, and    X is C—Q¹, then Y is not C—Q²;-   or a pharmaceutically acceptable salt thereof.

A fifth embodiment of the present invention is a compound of Formula I,wherein:

-   A is    -   (i) a monocyclic heterocycle selected from the group consisting        of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,        pyridyl, pyrazinyl, pyrimidinyl, pyrazidinyl, oxazolyl,        isooxazolyl, thiazolyl, isothiazolyl, pyrrolidinyl,        pyrazolidinyl, imidazolinyl, piperidinyl, piperazinyl,        thiazolidinyl, isothiazolidinyl, and morphonlinyl;    -   (ii) a fused bicyclic heterocycle selected from the group        consisting of indolyl, isoindolyl, phthalazinyl, purinyl,        quinoxalinyl, quinazolinyl, cinnolinyl, 1,6-naphthyridinyl,        1,8-napthyridinyl, benzimidazolyl, quinolinyl, isoquinolinyl,        indazolyl, dihydroindolyl, dihydroisoindolyl,        tetrahydroquinolyl, tetrahydroisoquinolyl,        imidazo[1,2-a]pyrimidinyl, 2,3-dihydroimidazo[2,        1b][1,3]thiazolyl, benzazepinyl, dihydrobenazepinyl,        benzodiazepinyl, dihydrobenzodiazepinyl,        tetrahydrobenzodiazepinyl, and benzothiazolyl; or    -   (iii) a fused tricyclic heterocycle selected from the group        consisting of phenothiazinyl, carbazolyl, beta-carbolinyl,        tetrahydro-beta-carbolinyl, acridinyl, phenazinyl, and        phenoxazinyl;-   and all other variables are as defined in the second embodiment;-   and with the proviso that when Z¹ is C—Q³, Z² is C—Q⁴, Z³ is CH, and    X is C—Q¹, then Y is not C—Q²;-   or a pharmaceutically acceptable salt thereof.

A sixth embodiment of the present invention is a compound of Formula I,wherein:

-   X is N;-   Y is C—Q²;-   Z¹ is C—Q³;-   Z² is C—Q⁴;-   Z³ is CH;-   Q² is    -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —C₁₋₆ fluoroalkyl,    -   (4) —O—C₁₋₆ alkyl,    -   (5) —O—C₁₋₆ fluoroalkyl,    -   (6) halo,    -   (7) —CN,    -   (8) —C₁₋₆ alkyl-OR^(a),    -   (9) —C₀₋₆ alkyl-C(═O)R^(a),    -   (10) —C₀₋₆ alkyl-CO₂R^(a),    -   (11) —C₀₋₆ alkyl-SR^(a),    -   (12) —N(R^(a))₂,    -   (13) —C₁₋₆ alkyl —N(R^(a))₂,    -   (14) —C₀₋₆ alkyl-C(═O)N(R^(a))₂,    -   (15) —C₁₋₆ alkyl-N(R^(a))—C(R^(a))═O,    -   (16) —SO₂R^(a),    -   (17) —N(R^(a))SO₂R^(a),    -   (18) —C₂₋₅ alkynyl,    -   (19) —C₂₋₅ alkynyl-CH₂N(R^(a))₂,    -   (20) —C₂₋₅ alkynyl-CH₂OR^(a),    -   (21)    -   (22) —N(R^(a))—C₁₋₆ alkyl-SR^(a),    -   (23) —N(R^(a))—C₁₋₆ alkyl-OR^(a),    -   (24) —N(R^(a))—C₁₋₆ alkyl-N(R^(a))₂,    -   (25) —N(R^(a))—C₁₋₆ alkyl-N(R^(a))—C(R^(a))═O,    -   (26) —R^(k),    -   (27) —C₁₋₆ alkyl substituted with R^(k),    -   (28) —C₁₋₆ fluoroalkyl substituted with R^(k),    -   (29) —C₂₋₅ alkenyl-R^(k),    -   (30) —C₂₋₅ alkynyl-R^(k),    -   (31) —O-R^(k),    -   (32) —O—C₁₋₄ alkyl-R^(k),    -   (33) —S(O)_(n)—R^(k),    -   (34) —S(O)_(n)—C₁₋₄ alkyl-R^(k),    -   (35) —O—C₁₋₆ alkyl-OR^(k),    -   (36) —O—C₁₋₆ alkyl-O—C₁₋₄ alkyl-R^(k),    -   (37) —O—C₁₋₆ alkyl-SR^(k),    -   (39) —N(R^(c))—C₁₋₆ alkyl substituted with one or two R^(k)        groups,    -   (40) —N(R^(c))—C₁₋₆ alkyl-OR^(k),    -   (41) —C(═O)N—C₁₋₆ alkyl-R^(k),    -   (42) —C₂₋₅ alkynyl-CH₂S(O)_(n)—R^(a), or    -   (43) —C(═NR^(a))—N(R^(a))₂;-   each of Q³ and Q⁴ is independently:    -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —C₁₋₆ fluoroalkyl,    -   (4) —O—C₁₋₆ alkyl,    -   (5) —O—C₁₋₆ fluoroalkyl,    -   (6) halo,    -   (7) —CN,    -   (8) —C₁₋₆ alkyl-OR^(a),    -   (9) —C₀₋₆ alkyl-C(═O)R^(a),    -   (10) —C₀₋₆ alkyl-CO₂R^(a),    -   (11) —SR^(a),    -   (12) —N(R^(a))₂,    -   (13) —C₁₋₆ alkyl —N(R^(a))₂,    -   (14) —C₀₋₆ alkyl-C(═O)N(R^(a))₂,    -   (15) —SO₂R^(a),    -   (16) —N(R^(a))SO₂R^(a);    -   (17) —R^(k), or    -   (18) —C₁₋₆ alkyl substituted with R^(k);-   and all other variables are as originally defined;-   or a pharmaceutically acceptable salt thereof.

A seventh embodiment is identical to the sixth embodiment, except thatall other variables are as defined in the first embodiment, instead ofbeing as originally defined.

An eighth embodiment of the present invention is a compound of FormulaI, wherein:

-   Q³ is:    -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —C₁₋₆ fluoroalkyl,    -   (4) —O—C₁₋₆ alkyl,    -   (5) —O—C₁₋₆ fluoroalkyl,    -   (6) halo,    -   (7) —CN,    -   (8) —C₁₋₆ alkyl-OR^(a),    -   (9) —C₀₋₆ alkyl-C(═O)R^(a),    -   (10) —C₀₋₆ alkyl-CO₂R^(a),    -   (11) —SR^(a),    -   (12) —N(R^(a))₂,    -   (13) —C₁₋₆ alkyl —N(R^(a))₂,    -   (14) —C₀₋₆ alkyl-C(═O)N(R^(a))₂,    -   (15) —SO₂R^(a),    -   (16) —N(R^(a))SO₂R^(a);    -   (17) —R^(k), or    -   (18) —C₁₋₆ alkyl substituted with R^(k);-   Q⁴ is:    -   (1) —H,    -   (2) —C₁₋₆ alkyl,    -   (3) —C₁₋₆ fluoroalkyl,    -   (4) —O—C₁₋₆ alkyl,    -   (5) —O—C₁₋₆ fluoroalkyl,    -   (6) halo,    -   (7) —CN,    -   (8) —C₁₋₆ alkyl-OR^(a),    -   (9) —C₀₋₆ alkyl-C(═O)R^(a),    -   (10) —C₀₋₆ alkyl-CO₂R^(a),    -   (11) —SR^(a),    -   (12) —N(R^(a))₂,    -   (13) —C₁₋₆ alkyl-N(R^(a))₂,    -   (14) —C₀₋₆ alkyl-C(═O)N(R^(a))₂,    -   (15) —SO₂R^(a), or    -   (16) —N(R^(a))SO₂R^(a);-   and all other variables are as defined in the seventh embodiment;-   or a pharmaceutically acceptable salt thereof.

In an aspect of each of the sixth, seventh and eighth embodiments, Q³and Q⁴ are both —H.

A ninth embodiment of the present invention is a compound of Formula(II):

wherein

-   A is    -   (i) a 4- to 7-membered saturated or unsaturated monocylic        heterocycle which contains from 1 to 4 nitrogen atoms, from zero        to 2 heteroatoms selected from oxygen and sulfur, and a balance        of carbon atoms, with at least one of the ring atoms being        carbon;    -   (ii) a 7- to 11-membered fused bicyclic heterocycle either ring        of which is saturated or unsaturated, wherein the fused bicyclic        heterocycle contains from 1 to 6 heteroatoms selected from        nitrogen, oxygen and sulfur, and a balance of carbon atoms with        at least two of the ring atoms being carbon; or    -   (iii) a 11- to 15-membered fused tricyclic heterocycle any ring        of which is saturated or unsaturated, wherein the fused        tricyclic heterocycle contains from 1 to 6 nitrogen atoms, from        zero to 3 heteroatoms selected from oxygen and sulfur, and a        balance of carbon atoms with at least three of the ring atoms        being carbon;-   L is    -   (i) a single bond;    -   (ii) —(CH₂)₁₋₃—, which is optionally substituted with 1 or 2        substituents independently selected from the group consisting of        —OH, —C₁₋₄ alkyl, —O—C₁₋₄ alkyl, —CO₂CH₃, —CO₂CH₂-phenyl,        phenyl, benzyl, —(CH₂)₁₋₂OH, —CH(OH)-phenyl, and        —CH(NH₂)-phenyl;    -   (iii) —(CH₂)₀₋₁—CH═CH—(CH₂)—, which is optionally substituted        with 1 or 2 substituents independently selected from the group        consisting of halogen, —OH, —C₁₋₄ alkyl, and —O—C₁₋₄ alkyl; or    -   (iv)    -    wherein u and v are each integers having a value of from 0 to        4, provided that the sum of u+v is 1, 2, 3 or 4;-   Z¹ is N or C—Q³;-   Q² is    -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —C₁₋₄ fluoroalkyl,    -   (4) —O—C₁₋₄ alkyl,    -   (5) —O—C₁₋₄ fluoroalkyl,    -   (6) halo,    -   (7) —CN,    -   (8) —C₁₋₄ alkyl-OR^(a),    -   (9) —(CH₂)₀₋₂C(═O)R^(a),    -   (10) —(CH₂)₀₋₂CO₂R^(a),    -   (11) —(CH₂)₀₋₂SR^(a),    -   (12) —N(R^(a))₂,    -   (13) —C₁₋₄ alkyl —N(R^(a))₂,    -   (14) —(CH₂)₀₋₂C(═O)N(R^(a))₂,    -   (15) —SO₂R^(a),    -   (16) —N(R^(a))SO₂R^(a),    -   (17) —C₂₋₃ alkynyl,    -   (18) —C≡C—CH₂N(R^(a))₂    -   (19) —C≡C—CH₂OR^(a)    -   (20) —N(R^(a))—C₁₋₄alkyl-SR^(a),    -   (21) —N(R^(a))—C₁₋₄ alkyl-OR^(a),    -   (22) —N(R^(a))—C₁₋₄ alkyl-N(R^(a))₂,    -   (23) —N(R^(a))—C₁₋₄ alkyl-N(R^(a))—C(R^(a))═O,    -   (24) —R^(k),    -   (25) —C₁₋₄ alkyl substituted with R^(k),    -   (26) —C₁₋₄ fluoroalkyl substituted with R^(k),    -   (27) —C₂₋₅ alkenyl-R^(k),    -   (28) —C₂₋₅ alkynyl-R^(k),    -   (29) —O-R^(k),    -   (30) —O—C₁₋₄ alkyl-R^(k),    -   (31) —S(O)_(n)—R^(k),    -   (32) —N(R^(c))—R^(k),    -   (33) —N(R^(c))—C₁₋₄ alkyl substituted with one or two R^(k)        groups,    -   (34) —N(R^(c))—C₁₋₄ alkyl-OR^(k),    -   (35) —C(═O)N—C₁₋₄ alkyl-R^(k),    -   (36) —C≡C—CH₂SR^(a), or    -   (37) C—C—CH₂SO₂R^(a);-   Q³ is    -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —C₁₋₄ fluoroalkyl,    -   (4) —O—C₁₋₁₄ alkyl,    -   (5) —O—C₁₋₄ fluoroalkyl,    -   (6) halo selected from —F, —Cl, and —Br,    -   (7) —CN,    -   (8) —C₁₋₄ alkyl-OR^(a), or    -   (9) —C₁₋₄ alkyl substituted with R^(k);-   Q⁴ is:    -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —C₁₋₄ fluoroalkyl,    -   (4) —O—C₁₋₄ alkyl,    -   (5) —O—C₁₋₄ fluoroalkyl,    -   (6) halo selected from —F, —Cl, and —Br,    -   (7) —CN,    -   (8) —C₁₋₆ alkyl-OR^(a),    -   (9) —N(R^(a))₂, or    -   (10) —C₁₋₆ alkyl —N(R^(a))₂;-   each of R¹ and R² is independently:    -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —C₁₋₄ fluoroalkyl,    -   (4) —O—C₁₋₄ alkyl,    -   (5) —O—C₁₋₄ fluoroalkyl,    -   (6) —OH,    -   (7) halo,    -   (8) —CN,    -   (9) —C₁₋₄ alkyl-OR^(a),    -   (10) —(CH₂)₀₋₂C(═O)R^(a),    -   (11) —(CH₂)₀₋₂CO₂R^(a),    -   (12) —(CH₂)₀₋₂SR^(a),    -   (13) —N(R^(a))₂,    -   (14) —C₁₋₄ alkyl N(R^(a))₂,    -   (15) —(CH₂)₀₋₂C(═O)N(R^(a))₂,    -   (16) —C₁₋₄ alkyl-N(R^(a))—C(R^(a))═O,    -   (17) —SO₂R^(a),    -   (18) —N(R^(a))SO₂R^(a),    -   (19) —O—C₁₋₄ alkyl-OR^(a),    -   (20) —O—C₁₋₄ alkyl-SR^(a),    -   (21) —O-C₁₋₄ alkyl-NH—CO₂R^(a),    -   (22) —O—C₂₋₄ alkyl-N(R^(a))₂,    -   (23) —N(R^(a))—C₁₋₄ alkyl-SR^(a),    -   (24) —N(R^(a))—C₁₋₄ alkyl-OR^(a),    -   (25) —N(R^(a))—C₁₋₄ alkyl-N(R^(a))₂,    -   (26) —N(R^(a))—C₁₋₄ alkyl-N(R^(a))—C(R^(a))═O,    -   (27) —R^(k),    -   (28) —C₁₋₄ alkyl substituted with 1 or 2 R^(k) groups,    -   (29) —C₁₋₄ fluoroalkyl substituted with 1 or 2 R^(k) groups,    -   (30) —O—R^(k),    -   (31) —O—C₁₋₄ alkyl-R^(k),    -   (32) —S(O)_(n)—R^(k),    -   (33) —S(O)_(n)-C₁₋₄ alkyl-R^(k),    -   (34) —O—C₁₋₄ alkyl-OR^(k),    -   (35) —O—C₁₋₄ alkyl-O—C₁₋₄ alkyl-R^(k),    -   (36) —O—C₁₋₄ alkyl-SR^(k), or    -   (37) —C₀₋₄ alkyl-N(R^(b))(R^(k));-   each of R³ and R⁴ is independently    -   (1) —H,    -   (2) halo,    -   (3) —CN,    -   (4) —OH,    -   (5) C₁₋₄ alkyl,    -   (6) C₁₋₄ fluoroalkyl,    -   (7) —O—C₁₋₄ alkyl,    -   (8) —O—C₁₋₄ fluoroalkyl,    -   (9) —C₁₋₄ alkyl-OR^(a),    -   (10) —O—C₁₋₄ alkyl-OR^(a),    -   (11) —O—C₁₋₄ alkyl-SR^(a),    -   (12) —O—C₁₋₄ alkyl-NH—CO₂R^(a), or    -   (13) —O—C₂₋₄ alkyl-N(R^(a))₂;-   R⁵ is    -   (1) —H,    -   (2) —C₁₋₄ alkyl, optionally substituted with 1 or 2 substituents        independently selected from halogen, —O—C₁₋₄ alkyl, —O—C₁₋₄        fluoroalkyl, —N(R^(a))₂, and —C₀₋₂R^(a);    -   (3) phenyl optionally substituted with from 1 to 3 substituents        independently selected from halogen, C₁₋₄ alkyl, C₁₋₄        fluoroalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ fluoroalkyl, —S—C₁₋₄ alkyl,        —CN, and —OH, or    -   (4) —C₁₋₄ alkyl substituted with phenyl;-   each R^(a) is independently —H or —C₁₋₄ alkyl;-   each R^(b) is independently:    -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —C₁₋₄ fluoroalkyl,    -   (4) —R^(k),    -   (5) —C₁₋₄ alkyl-R^(k),    -   (6) —S(O)_(n)—R^(k), or    -   (7) —C(═O)-R^(k);-   each R^(c) is independently    -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —C₁₋₄ alkyl substituted with —N(R^(a))₂, or    -   (4) —C₁₋₄ alkyl-phenyl, wherein the phenyl is optionally        substituted with 1 to 3 substituents independently selected from        halogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄        fluoroalkyl, —S—C₁₋₄ alkyl, —CN, and —OH;-   each R^(k) is independently:    -   (1) aryl selected from phenyl and naphthyl, wherein aryl is        unsubstituted or substituted with from 1 to 5 substituents        independently selected from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) C₁₋₆ fluoroalkyl,        -   (d) —O—C₁₋₆ alkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) phenyl,        -   (g) —S—C₁₋₆ alkyl,        -   (h) —CN,        -   (i) —OH,        -   (j) phenyloxy, unsubstituted or substituted with from 1 to 3            substituents independently selected from:            -   (i) halogen,            -   (ii) C₁₋₆ alkyl,            -   (iii) C₁₋₆ fluoroalkyl, and            -   (iv) —OH,        -   (k) —N(R^(a))₂,        -   (l) —C₁₋₆ alkyl-N(R^(a))₂,        -   (m) —R^(t),        -   (p) —(CH₂)₀₋₃C(═O)N(R^(a))₂, and        -   (q) —(CH₂)₀₋₃C(═O)R^(a);    -   (2) —C₃₋₇ cycloalkyl, unsubstituted or substituted with from 1        to 3 substituents independently selected from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) —O—C₁₋₆ alkyl,        -   (d) C₁₋₆ fluoroalkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) —CN,        -   (h) phenyl, and        -   (j) —OH;    -   (3) —C₃₋₇ cycloalkyl fused with a phenyl ring, unsubstituted or        substituted with from 1 to 5 substituents independently selected        from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) —O—C₁₋₆ alkyl,        -   (d) C₁₋₆ fluoroalkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) —CN, and        -   (g) —OH;    -   (4) a 5- or 6-membered heteroaromatic ring containing from 1 to        4 heteroatoms independently selected from oxygen, nitrogen and        sulfur, wherein the heteroaromatic ring is unsubstituted or        substituted on nitrogen or carbon with from 1 to 5 substituents        independently selected from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) C₁₋₆ fluoroalkyl,        -   (d) —O—C₁₋₆ alkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) phenyl,        -   (g) —S—C₁₋₆ alkyl,        -   (h) —CN,        -   (i) —OH,        -   (j) phenyloxy, unsubstituted or substituted with from 1 to 3            substituents independently selected from:            -   (i) halogen,            -   (ii) C₁₋₆ alkyl,            -   (iii) C₁₋₆ fluoroalkyl, and            -   (iv) —OH,        -   (k) —N(R^(a))₂,        -   (l) —C₁₋₆ alkyl-N(R^(a))₂,        -   (m) —R^(t),        -   (n) oxo,        -   (o)—(CH₂)₀₋₃C(═O)N(R^(a))₂, and        -   (p) —(CH₂)₀₋₃C(═O)R^(a);    -   (5) a 5- or 6-membered saturated heterocyclic ring containing 1        or 2 heteroatoms independently selected from oxygen, nitrogen        and sulfur, wherein the heterocyclic ring is unsubstituted or        substituted with from 1 to 4 substituents independently selected        from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) —O—C₁₋₆ alkyl,        -   (d) C₁₋₆ fluoroalkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) —CN,        -   (g) oxo,        -   (h) phenyl,        -   (i) benzyl,        -   (j) phenylethyl,        -   (k) —OH,        -   (l) —(CH₂)₀₋₃C(═O)N(R^(a))₂,        -   (m) —(CH₂)₀₋₃C(═O)R^(a),        -   (n) —N(R^(a))—C(═O)R^(a),        -   (o) —N(R^(a))—C(═O)OR^(a),        -   (p) —(CH₂)₁₋₃N(R^(a))—C(═O)R^(a),        -   (q) —N(R^(a))₂,        -   (r) —(CH₂)₁₋₃N(R^(a))₂,        -   (s) —(CH₂)₀₋₃C(═O)R^(t),        -   (t) —R^(t),        -   (u) —N(R^(a))R^(t), and        -   (v) —(CH₂)₁₋₃R^(t); or    -   (6) an 8- to 10-membered heterobicyclic ring containing from 1        to 4 heteroatoms independently selected from oxygen, nitrogen        and sulfur, wherein the heterobicyclic ring is saturated or        unsaturated, and is unsubstituted or substituted with from 1 to        5 substituents independently selected from:        -   (a) halogen,        -   (b) C₁₋₆ alkyl,        -   (c) —O—C₁₋₆ alkyl,        -   (d) C₁₋₆ fluoroalkyl,        -   (e) —O—C₁₋₆ fluoroalkyl,        -   (f) —CN,        -   (g) ═O, and        -   (h) —OH;-   R^(t) is naphthyl or a 5- or 6-membered heteromonocylic ring    containing from 1 to 4 nitrogen atoms, wherein the heteromonocyclic    ring is saturated or unsaturated, and wherein the naphthyl or the    heteromonocyclic ring is unsubstituted or substituted with 1 or 2    substituents independently selected from halogen, oxo, C₁₋₄ alkyl,    and —O—C₁₋₄ alkyl; and-   n is an integer equal to 0, 1 or 2;-   or a pharmaceutically acceptable salt thereof.

A tenth embodiment of the present invention is a compound of Formula II,wherein

-   Z¹ is CH;-   Q² is    -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —(CH₂)₀₋₂CF₃,    -   (4) —O—C₁₋₄ alkyl,    -   (5) —O—(CH₂)₀₋₂CF₃,    -   (6) halo selected from —F, —Cl and —Br,    -   (7) —CN,    -   (8) —(CH₂)₁₋₃OR^(a),    -   (9) —(CH₂)₀₋₂C(═O)R^(a),    -   (10) —(CH₂)₀₋₂CO₂R^(a),    -   (11) —(CH₂)₀₋₂SR^(a),    -   (12) —N(R^(a))₂,    -   (13) —(CH₂)₁₋₃N(R^(a))₂,    -   (14) —(CH₂)₀₋₂C(═O)N(R^(a))₂,    -   (15) —SO₂R^(a),    -   (16) —N(R^(a))SO₂R^(a),    -   (17) —C≡C—CH₂OR^(a)    -   (18) —N(R^(a))—(CH₂)₁₋₄SR^(a),    -   (19) —N(R^(a))—(CH₂)₁₋₄OR^(a),    -   (20) —N(R^(a))—(CH₂)₁₋₄—N(R^(a))₂,    -   (21) —N(R^(a))—(CH₂)₁₋₄N(R^(a))—C(R^(a))═O,    -   (22) —R^(k),    -   (23) —(CH₂)₁R^(k),    -   (24) —C≡C—CH₂R^(k),    -   (25) —O—R^(k),    -   (26) —S(O)_(n)—R^(k),    -   (27) —N(R^(c))—R^(k),    -   (28) —N(R^(c))—(CH₂)₁₋₄H substituted with one or two R^(k)        groups,    -   (29) —N(R^(c))—(CH₂)₁₋₄OR^(k),    -   (30) —C(═O)N—(CH₂)₁₋₄R^(k),    -   (31) —C≡C—CH₂SR^(a), or    -   (32) —C≡C—CH₂SO₂R^(a);-   Q⁴ is —H;-   each of R¹ and R² is independently:    -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —(CH₂)₀₋₂CF₃,    -   (4) —O—C₁₋₄ alkyl,    -   (5) —O—(CH₂)₀₋₂CF₃,    -   (6) —OH,    -   (7) halo selected from —F, —Cl and —Br,    -   (8) —CN,    -   (9) —(CH₂)₁₋₃OR^(a),    -   (10) —(CH₂)₀₋₂C(═O)R^(a),    -   (11) —(CH₂)₀₋₂CO₂R^(a),    -   (12) —(CH₂)₀₋₂SR^(a),    -   (13) —N(R^(a))₂,    -   (14) —(CH₂)₁₋₃N(R^(a))₂,    -   (15) —(CH₂)₀₋₂C(═O)N(R^(a))₂,    -   (16) —C₁₋₄ alkyl-N(R^(a))—C(R^(a))═O,    -   (17) —SO₂R^(a),    -   (18) —N(R^(a))SO₂R^(a),    -   (19) —O—(CH₂)₁₋₄OR^(a),    -   (20) —O—(CH₂)₁₋₄SR^(a),    -   (21) —O—(CH₂)₁₋₄NH—CO₂R^(a),    -   (22) —O—(CH₂)₂₋₄N(R^(a))₂,    -   (23) —N(R^(a))—(CH₂)₁₋₄SR^(a),    -   (24) —N(R^(a))—(CH₂)₁₋₄OR^(a),    -   (25) —N(R^(a))—(CH₂)₁₋₄N(R^(a))₂,    -   (26) —N(R^(a))—(CH₂)₁₋₄N(R^(a))—C(R^(a))═O,    -   (27) —R^(k),    -   (28) —(CH₂)₁₋₄H substituted with 1 or 2 R^(k) groups,    -   (29) —O—R^(k),    -   (30) —O—(CH₂)₁₄R^(k),    -   (31) —S(O)_(n)—R^(k),    -   (32) —S(O)_(n)—(CH₂)₁₋₄R^(k),    -   (33) —O—(CH₂)₁₋₄OR^(k),    -   (34) —O—(CH₂)₁₋₄—O—(CH₂)₁₋₄R^(k),    -   (35) —O—(CH₂)₁₋₄SR^(k), or    -   (36) —(CH₂)₀₋₄N(R^(b))(R^(k));-   each of R³ and R⁴ is independently    -   (1) —H,    -   (2) halo selected from —F, —Cl and —Br,    -   (3) —CN,    -   (4) —OH,    -   (5) C₁₋₄ alkyl,    -   (6) —(CH₂)₀₋₂CF₃,    -   (7) —O—C₁₋₄ alkyl, or    -   (8) —O(CH₂)₀₋₂CF₃,-   R⁵ is    -   (1) —H.    -   (2) —C₁₋₄ alkyl,    -   (3) —(CH₂)₁₋₄N(R^(a))₂,    -   (4) —(CH₂)₁₋₄CO₂R^(a),    -   (5) phenyl optionally substituted with from 1 to 3 substituents        independently selected from halogen, C₁₋₄ alkyl, —(CH₂)₀₋₂CF₃,        —O—C₁₋₄ alkyl, —O(CH₂)₀₋₂CF₃, —S—C₁₋₄ alkyl, —CN, and —OH, or    -   (6) —(CH₂)₁₋₄-phenyl;-   each R^(a) is independently —H or —C₁₋₄ alkyl;-   each R^(b) is independently:    -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —CF₃,    -   (4) —R^(k), or    -   (5) —(CH₂)₁₋₄—R^(k);-   each R^(c) is independently    -   (1) —H,    -   (2) —C₁₋₄ alkyl,    -   (3) —(CH₂)₁₋₄N(R^(a))₂, or    -   (4) —(CH₂)₁₋₄-phenyl, wherein the phenyl is optionally        substituted with 1 to 3 substituents independently selected from        halogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄        fluoroalkyl, —S—C₁₋₄ alkyl, —CN, and —OH; and-   each R^(k) is independently:    -   (1) aryl selected from phenyl and naphthyl, wherein aryl is        unsubstituted or substituted with from 1 to 4 substituents        independently selected from:        -   (a) halogen,        -   (b) C₁₋₄ alkyl,        -   (c) C₁₋₄ fluoroalkyl,        -   (d) —O—C₁₋₄ alkyl,        -   (e) —O—C₁₋₄ fluoroalkyl,        -   (f) phenyl,        -   (g) —S—C₁₋₄ alkyl,        -   (h) —CN,        -   (i) —OH,        -   (j) phenyloxy, unsubstituted or substituted with from 1 to 3            substituents independently selected from:            -   (i) halogen,            -   (ii) C₁₋₄ alkyl,            -   (iii) C₁₋₄ fluoroalkyl, and            -   (iv) —OH,        -   (k) —N(R^(a))₂,        -   (l) —C₁₋₄ alkyl-N(R^(a))₂,        -   (m) —R^(t),        -   (p) —(CH₂)₀₋₃C(═O)N(R^(a))₂, and        -   (q) —(CH₂)₀₋₃C(═O)R^(a);    -   (2) —C₃₋₆ cycloalkyl, unsubstituted or substituted with from 1        to 3 substituents independently selected from:        -   (a) halogen,        -   (b) C₁₋₄ alkyl,        -   (c) —O—C₁₋₄ alkyl,        -   (d) C₁₋₄ fluoroalkyl,        -   (e) —O—C₁₋₄ fluoroalkyl,        -   (f) —CN,        -   (h) phenyl, and        -   (j) —OH;    -   (3) —C₃₋₆ cycloalkyl fused with a phenyl ring, unsubstituted or        substituted with from 1 to 4 substituents independently selected        from:        -   (a) halogen,        -   (b) C₁₋₄ alkyl,        -   (c) —O—C₁₋₄ alkyl,        -   (d) C₁₋₄ fluoroalkyl,        -   (e) —O—C₁₋₄ fluoroalkyl,        -   (f) —CN, and        -   (g) —OH;    -   (4) a 5- or 6-membered heteroaromatic ring selected from        thienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolyl,        isothiazolyl, oxazolyl, isooxazolyl, pyrazinyl, pyrimidinyl,        triazolyl, tetrazolyl, furanyl, and pyridazinyl, wherein the        heteroaromatic ring is unsubstituted or substituted on nitrogen        or carbon with from 1 to 4 substituents independently selected        from:        -   (a) halogen,        -   (b) C₁₋₄ alkyl,        -   (c) C₁₋₄ fluoroalkyl,        -   (d) —O—C₁₋₄ alkyl,        -   (e) —O—C₁₋₄ fluoroalkyl,        -   (f) phenyl,        -   (g) —S—C₁₋₄ alkyl,        -   (h) —CN,        -   (i) —OH,        -   (j) phenyloxy, unsubstituted or substituted with from 1 to 3            substituents independently selected from:            -   (i) halogen,            -   (ii) C₁₋₄ alkyl,            -   (iii) C₁₋₄ fluoroalkyl, and            -   (iv) —OH,        -   (k) —N(R^(a))₂,        -   (l) —C₁₋₄ alkyl-N(R^(a))₂,        -   (m) —R^(t),        -   (n) oxo,        -   (o)—(CH₂)₀₋₃C(═O)N(R^(a))₂, and        -   (p) —(CH₂)₀₋₃C(═O)R^(a);    -   (5) a 5- or 6-membered saturated heterocyclic ring selected from        piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,        isothiazolidinyl, oxazolidinyl, isooxazolidinyl, pyrrolidinyl,        imidazolidinyl, piperazinyl, tetrahydrofuranyl, and        pyrazolidinyl, wherein the heterocyclic ring is unsubstituted or        substituted with from 1 to 3 substituents independently selected        from:        -   (a) halogen,        -   (b) C₁₋₄ alkyl,        -   (c) —O—C₁₋₄ alkyl,        -   (d) C₁₋₄ fluoroalkyl,        -   (e) —O—C₁₋₄ fluoroalkyl,        -   (f) —CN,        -   (g) ═O,        -   (h) phenyl,        -   (i) benzyl,        -   (j) phenylethyl,        -   (k) —OH,        -   (l) —(CH₂)₀₋₃C(═O)N(R^(a))₂,        -   (m) —(CH₂)₀₋₃C(═O)R^(a),        -   (n) N(R^(a))—C(═O)R^(a),        -   (o) N(R^(a))—C(═O)OR^(a),        -   (p) (CH₂)₁₋₃N(R^(a))—C(═O)R^(a),        -   (q) N(R^(a))₂,        -   (r) (CH₂))₁₋₃N(R^(a))₂,        -   (s) —(CH₂)₀₋₃C(═O)R^(t),        -   (t) —R^(t),        -   (u) —N(R^(a))R^(t), and        -   (v) —(CH₂)₁₋₃R^(t); or    -   (6) an 8- to 10-membered heterobicyclic ring selected from        indolyl, benzotriazolyl, benzoimidazolyl,        imidazo[4,5-b]pyridinyl, dihydroimidazo[4,5-b]pyridinyl,        pyrazolo[4,3-c]pyridinyl, dihydropyrazolo[4,3c]pyridinyl,        tetrahydropyrazolo[4,3-c]pyridinyl, pyrrolo[1,2-a]pyrazinyl,        dihydropyrrolo[1,2-a]pyrazinyl,        tetrahydropyrrolo[1,2-a]pyrazinyl,        octahydropyrrolo[1,2-a]pyrazinyl, isoindolyl, indazolyl,        indolinyl, isoindolinyl, quinolinyl, isoquinolinyl,        quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, and        isochromanyl, wherein the bicyclic ring is unsubstituted or        substituted with 1 or 2 substituents independently selected        from:        -   (a) halogen,        -   (b) C₁₋₄ alkyl,        -   (c) —O—C₁₋₄ alkyl,        -   (d) C₁₋₄ fluoroalkyl,        -   (e) —O—C₁₋₄ fluoroalkyl,        -   (f) —CN,        -   (g) ═O, and        -   (h) —OH;-   R^(t) is naphthyl or a 5- or 6-membered heteromonocylic ring    selected from pyrrolidinyl, pyrazolidinyl, imidazolinyl,    piperidinyl, piperazinyl, pyrrolyl, pyridyl, imidazolyl, pyrazolyl,    triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, and pyradizinyl;-   and wherein the naphthyl or the heteromonocyclic ring is    unsubstituted or substituted with 1 or 2 substituents independently    selected from halogen, oxo, C₁₋₄ alkyl, and —O—C₁₋₄ alkyl;-   and all other variables are as defined in the ninth embodiment;-   or a pharmaceutically acceptable salt thereof.

A first class of the present invention is compounds of Formula (III)

wherein

-   A is    -   (i) a 4- to 7-membered saturated or unsaturated monocylic        heterocycle which contains from 1 to 4 nitrogen atoms, from zero        to 2 heteroatoms selected from oxygen and sulfur, and a balance        of carbon atoms, with at least one of the ring atoms being        carbon;    -   (ii) a 7- to 11-membered fused bicyclic heterocycle either ring        of which is saturated or unsaturated, wherein the fused bicyclic        heterocycle contains from 1 to 6 heteroatoms selected from        nitrogen, oxygen and sulfur, and a balance of carbon atoms with        at least two of the ring atoms being carbon; or    -   (iii) a 11- to 15-membered fused tricyclic heterocycle any ring        of which is saturated or unsaturated, wherein the fused        tricyclic heterocycle contains from 1 to 6 nitrogen atoms, from        zero to 3 heteroatoms selected from oxygen and sulfur, and a        balance of carbon atoms with at least three of the ring atoms        being carbon;-   L is    -   (i) a single bond; or    -   (ii) —(CH₂)₁₋₃—, which is optionally substituted with 1 or 2        substituents independently selected from the group consisting of        —OH, methyl, ethyl, —CO₂CH₃, —CO₂CH₂-phenyl, phenyl, benzyl,        —(CH₂)₁₋₂OH, —CH(OH)-phenyl, and —CH(NH₂)-phenyl;-   Q² is    -   (1) —H,    -   (2) methyl,    -   (3) ethyl,    -   (4) CF₃,    -   (5) methoxy,    -   (6) ethoxy    -   (7) —OCF₃    -   (8) halo selected from —F, —Cl and —Br,    -   (9) —CN,    -   (10) —CH₂OH,    -   (11) —CH₂OCH₃    -   (12) —(CH₂)₀₋₂CO₂CH₃,    -   (13) —SR^(a),    -   (14) —N(R^(a))₂,    -   (15) —SO₂R^(a),    -   (16) —C≡C—CH₂OR^(a)    -   (17) —N(R^(a))—(CH₂)₁₋₃SR^(a),    -   (18) —N(R^(a))—(CH₂)₁₋₃OR^(a),    -   (19) —N(R^(a))—(CH₂)₁₋₃N(R^(a))₂,    -   (20) —N(R^(a))—(CH₂)₁₋₃N(R^(a))—C(R^(a))═O,    -   (21) —R^(k),    -   (22) —(CH₂)₁₋₄R^(k),    -   (23) —C≡C—CH₂R^(k),    -   (24) —O—R^(k),    -   (25) —S—R^(k),    -   (26) —SO₂—R^(k),    -   (27) —N(R^(c))—R^(k),    -   (28) —N(R^(c))—(CH₂)₁₋₄H substituted with one or two R^(k)        groups,    -   (29) —N(R^(c))—(CH₂)₁₋₄OR^(k),    -   (30) —C(═O)N—(CH₂)₁₋₄R^(k),    -   (31) —C≡C—CH₂SR^(a), or    -   (32) —C≡C—CH₂SO₂R^(a);-   each of R¹ and R² is independently:    -   (1) —H,    -   (2) methyl,    -   (3) ethyl,    -   (4) CF₃,    -   (5) methoxy,    -   (6) ethoxy    -   (7) —OCF₃    -   (8) halo selected from —F, —Cl and —Br,    -   (9) —CN,    -   (10) —CH₂OR^(a),    -   (11) —CO₂R^(a),    -   (12) —SR^(a),    -   (13) —N(R^(a))₂,    -   (14) —(CH₂)₁₋₃N(R^(a))₂,    -   (15) —SO₂R^(a),    -   (16) —(CH₂)₁₋₂N(R^(a))—C(R^(a))═O,    -   (17) —R^(k),    -   (18) —(CH₂)₁₋₃H substituted with 1 or 2 R^(k) groups,    -   (19) —O—R^(k), or    -   (20) —O—(CH₂)₁₋₃R^(k);-   R⁵ is    -   (1) —H,    -   (2) methyl,    -   (3) —(CH₂)₁₋₂N(R^(a))₂,    -   (4) —(CH₂)₁₋₂CO₂CH₃, or    -   (5) —(CH₂)₁₋₂CO₂CH₂CH₃;    -   (6) phenyl, or    -   (7) benzyl;-   each R^(a) is independently —H or —C₁₋₄ alkyl;-   each R^(c) is independently —H, —C₁₋₄ alkyl, or —(CH₂)₁₋₃N(R^(a))₂;-   each R^(k) is independently:    -   (1) phenyl which is unsubstituted or substituted with from 1 to        4 substituents independently selected from:        -   (a) halogen selected from —F, —Cl, and —Br,        -   (b) methyl,        -   (c) —CF₃,        -   (d) methoxy,        -   (e) —OCF₃,        -   (f) phenyl,        -   (g) —S—CH₃,        -   (h) —CN,        -   (i) —OH,        -   (j) phenyloxy, unsubstituted or substituted with from 1 to 3            substituents independently selected from:            -   (i) halogen selected from —F, —Cl, and —Br,            -   (ii) methyl,            -   (iii) —CF₃, and            -   (iv) —OH,        -   (k) —N(R^(a))₂,        -   (l) —(CH₂)₁₋₃N(R^(a))₂,        -   (m) —R^(t),        -   (p) —(CH₂)₀₋₃C(═O)N(R^(a))₂, and        -   (q) —(CH₂)₀₋₃C(═O)R^(a);    -   (2) —C₃₋₆ cycloalkyl, unsubstituted or substituted with from 1        to 3 substituents independently selected from:        -   (a) halogen selected from —F, —Cl, and —Br,        -   (b) methyl,        -   (c) —CF₃,        -   (d) methoxy,        -   (e) —OCF₃,        -   (f) —CN,        -   (h) phenyl, and        -   (j) —OH;    -   (3) a 5- or 6-membered heteroaromatic ring selected from        thienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolyl,        isothiazolyl, oxazolyl, isooxazolyl, pyrazinyl, pyrimidinyl,        triazolyl, tetrazolyl, furanyl, and pyridazinyl, wherein the        heteroaromatic ring is unsubstituted or substituted on nitrogen        or carbon with 1 or 2 substituents independently selected from:        -   (a) halogen selected from —F, —Cl, and —Br,        -   (b) methyl,        -   (c) —CF₃,        -   (d) methoxy,        -   (e) —OCF₃,        -   (f) phenyl,        -   (g) —S—C₁₋₆ alkyl,        -   (h) —CN,        -   (i) —OH,        -   (j) phenyloxy, unsubstituted or substituted with from 1 to 3            substituents independently selected from:            -   (i) halogen selected from —F, —Cl, and —Br,            -   (ii) methyl,            -   (iii) —CF₃, and            -   (iv) —OH,        -   (k) —N(R^(a))₂,        -   (l) —C₁₋₆ alkyl-N(R^(a))₂,        -   (m) —R^(t),        -   (n) oxo,        -   (o) —(CH₂)₀₋₃C(═O)N(R^(a))₂, and        -   (p) —(CH₂)₀₋₃C(═O)R^(a);    -   (4) a 5- or 6-membered saturated heterocyclic ring selected from        piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,        isothiazolidinyl, oxazolidinyl, isooxazolidinyl, pyrrolidinyl,        imidazolidinyl, piperazinyl, tetrahydrofuranyl, and        pyrazolidinyl, wherein the heterocyclic ring is unsubstituted or        substituted with 1 or 2 substituents independently selected        from:        -   (a) halogen selected from —F, —Cl, and —Br,        -   (b) methyl,        -   (c) —CF₃,        -   (d) methoxy,        -   (e) —OCF₃,        -   (f) —CN,        -   (g) ═O,        -   (h) phenyl,        -   (i) benzyl,        -   (j) phenylethyl,        -   (k) —OH,        -   (l) —(CH₂)₀₋₃C(═O)N(R^(a))₂,        -   (m) —(CH₂)₀₋₃C(═O)R^(a),        -   (n) N(R^(a))—C(═O)R^(a),        -   (o) N(R^(a))—C(═O)OR^(a),        -   (p) (CH₂)₁₋₃N(R^(a))—C(═O)R^(a),        -   (q) N(R^(a))₂,        -   (r) (CH₂)₁₋₃N(R^(a))₂,        -   (s) —(CH₂)₀₋₃C(═O)R^(t),        -   (t) —R^(t),        -   (u) —N(R^(a))R^(t), and        -   (v) —(CH₂)₁₋₃R^(t); and    -   (5) an 8- to 10-membered heterobicyclic ring selected from        indolyl, benzotriazolyl, benzoimidazolyl,        imidazo[4,5-b]pyridinyl, dihydroimidazo[4,5-b]pyridinyl,        pyrazolo[4,3-c]pyridinyl, dihydropyrazolo[4,3c]pyridinyl,        tetrahydropyrazolo[4,3-c]pyridinyl, pyrrolo[1,2-a]pyrazinyl,        dihydropyrrolo[1,2-a]pyrazinyl,        tetrahydropyrrolo[1,2-a]pyrazinyl,        octahydropyrrolo[1,2-a]pyrazinyl, isoindolyl, indazolyl,        indolinyl, isoindolinyl, quinolinyl, isoquinolinyl,        quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, and        isochromanyl, wherein the bicyclic ring is unsubstituted or        substituted with 1 or 2 substituents independently selected        from:        -   (a) halogen selected from —F, —Cl, and —Br,        -   (b) methyl,        -   (c) —CF₃,        -   (d) methoxy,        -   (e) —OCF₃,        -   (f) —CN,        -   (g) ═O, and        -   (h) —OH;-   R^(t) is selected from pyrrolidinyl, pyrazolidinyl, imidazolinyl,    piperidinyl, piperazinyl, pyrrolyl, pyridyl, imidazolyl, pyrazolyl,    triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, and pyradizinyl; any    one of which is unsubstituted or substituted with 1 or 2    substituents independently selected from —F, —Cl, —Br, oxo, methyl,    and methoxy;-   or a pharmaceutically acceptable salt thereof.

A second class of the present invention is compounds of Formula (IV):

wherein

-   A is    -   (i) a monocyclic heterocycle selected from the group consisting        of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,        pyridyl, pyrazinyl, pyrimidinyl, pyrazidinyl, oxazolyl,        isooxazolyl, thiazolyl, isothiazolyl, pyrrolidinyl,        pyrazolidinyl, imidazolinyl, piperidinyl, piperazinyl,        thiazolidinyl, isothiazolidinyl, and morpholinyl;    -   (ii) a fused bicyclic heterocycle selected from the group        consisting of indolyl, isoindolyl, phthalazinyl, purinyl,        quinoxalinyl, quinazolinyl, cinnolinyl, 1,6-naphthyridinyl,        1,8-napthyridinyl, benzimidazolyl, quinolinyl, isoquinolinyl,        indazolyl, dihydroindolyl, dihydroisoindolyl,        tetrahydroquinolyl, tetrahydroisoquinolyl,        imidazo[1,2-a]pyrimidinyl,        2,3-dihydroimidazo[2,1b][1,3]thiazolyl, benzazepinyl,        dihydrobenazepinyl, benzodiazepinyl, dihydrobenzodiazepinyl,        tetrahydrobenzodiazepinyl, and benzothiazolyl; or    -   (iii) a fused tricyclic heterocycle selected from the group        consisting of phenothiazinyl, carbazolyl, beta-carbolinyl,        tetrahydro-beta-carbolinyl, acridinyl, phenazinyl, and        phenoxazinyl;-   each R^(k) is independently:    -   (1) phenyl which is unsubstituted or substituted with from 1 to        2 substituents independently selected from:        -   (a) halogen selected from —F, —Cl, and —Br,        -   (b) methyl,        -   (c) —CF₃,        -   (d) methoxy,        -   (e) —OCF₃,        -   (f) phenyl,        -   (g) —S—CH₃,        -   (h) —CN,        -   (i) —OH,        -   (j) phenyloxy        -   (k) —N(R^(a))₂,        -   (l) —(CH₂)₁₋₃N(R^(a))₂,        -   (m) —R^(t),        -   (p) —(CH₂)₀₋₃C(═O)N(R^(a))₂, and        -   (q) —(CH₂)₀₋₃C(═O)R^(a);    -   (2) —C₃₋₆ cycloalkyl;    -   (3) a 5- or 6-membered heteroaromatic ring selected from        thienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolyl,        isothiazolyl, pyrazinyl, pyirimidinyl, triazolyl, and        tetrazolyl, wherein the heteroaromatic ring is unsubstituted or        substituted on nitrogen or carbon with 1 or 2 substituents        independently selected from:        -   (a) halogen selected from —F, —Cl, and —Br,        -   (b) methyl,        -   (c) —CF₃,        -   (d) methoxy,        -   (e) —OCF₃,        -   (f) —S—C₁₋₆ alkyl,        -   (g) —CN,        -   (h) —OH,        -   (i) —N(R^(a))₂,        -   (j) —C₁₋₆ alkyl-N(R^(a))₂,        -   (k) —R^(t),        -   (l) oxo,        -   (m) —(CH₂)₀₋₃C(═O)N(R^(a))₂, and        -   (n) —(CH₂)₀₋₃C(═O)R^(a);    -   (4) a 5- or 6-membered saturated heterocyclic ring selected from        piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,        isothiazolidinyl, oxazolidinyl, isooxazolidinyl, pyrrolidinyl,        imidazolidinyl and, piperazinyl, wherein the heterocyclic ring        is unsubstituted or substituted with 1 or 2 substituents        independently selected from:        -   (a) halogen selected from —F, —Cl, and —Br,        -   (b) methyl,        -   (c) —CF₃,        -   (d) methoxy,        -   (e) —OCF₃,        -   (f) —CN,        -   (g) ═O,        -   (h) phenyl,        -   (i) benzyl,        -   (j) phenylethyl,        -   (k) —OH,        -   (l) —(CH₂)₀₋₃C(═O)N(R^(a))₂,        -   (m) —(CH₂)₀₋₃C(═O)R^(a),        -   (n) N(R^(a))—C(═O)R^(a),        -   (o) N(R^(a))—C(═O)OR^(a),        -   (p) (CH₂) ₁₋₃N(R^(a))—C(═O)R^(a),        -   (q) N(R^(a))₂,        -   (r) (CH₂)₁₋₃N(R^(a))₂,        -   (s) —(CH₂)₀₋₃C(O)R^(t),        -   (t) —R^(t),        -   (u) —N(R^(a))R^(t), and        -   (v) —(CH₂)₁₋₃R^(t); and    -   (5) an 8- to 10-membered heterobicyclic ring selected from        indolyl, imidazo[4,5-b]pyridinyl,        dihydroimidazo[4,5-b]pyridinyl, pyrazolo[4,3c]pyridinyl,        dihydropyrazolo[4,3-c]pyridinyl,        tetrahydropyrazolo[4,3-c]pyridinyl, pyrrolo[1,2-a]pyrazinyl,        dihydropyrrolo[1,2-a]pyrazinyl,        tetrahydropyrrolo[1,2a]pyrazinyl,        octahydropyrrolo[1,2-a]pyrazinyl, isoindolyl, indazolyl,        indolinyl, isoindolinyl, quinolinyl, isoquinolinyl,        quinoxalinyl, and quinazolinyl, wherein the bicyclic ring is        unsubstituted or substituted with 1 or 2 substituents        independently selected from:        -   (a) halogen selected from —F, —Cl, and —Br,        -   (b) methyl,        -   (c) —CF₃,        -   (d) methoxy,        -   (e) —OCF₃,        -   (f) —CN,        -   (g) ═O, and        -   (h) —OH; and-   R^(t) is selected from pyrrolidinyl, pyrazolidinyl, imidazolinyl,    piperidinyl, piperazinyl, pyrrolyl, pyridyl, imidazolyl, pyrazolyl,    triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, and pyradizinyl; any    one of which is unsubstituted or substituted with 1 or 2    substituents independently selected from —F, —Cl, —Br, oxo, methyl,    and methoxy;-   and all other variables are as defined in the first class;-   or a pharmaceutically acceptable salt thereof.

A first sub-class of the present invention is compounds of Formula IV,wherein:

-   A is    -   (i) a monocyclic heterocycle selected from the group consisting        of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,        pyridyl, oxazolyl, isooxazolyl, thiazolyl, pyrrolidinyl,        piperidinyl, piperazinyl, thiazolidinyl, and morphonlinyl;    -   (ii) a fused bicyclic heterocycle selected from the group        consisting of indolyl, isoindolyl, phthalazinyl, benzimidazolyl,        quinolinyl, isoquinolinyl, dihydroindolyl, dihydroisoindolyl,        tetrahydroquinolyl, tetrahydroisoquinolyl,        imidazo[1,2-a]pyrimidinyl,        2,3-dihydroimidazo[2,1-b][1,3]thiazolyl, benzazepinyl,        dihydrobenazepinyl, benzodiazepinyl, dihydrobenzodiazepinyl,        benzothiazolyl and tetrahydrobenzodiazepinyl; or    -   (iii) a fused tricyclic heterocycle selected from the group        consisting of phenothiazinyl, beta-carbolinyl, and        tetrahydro-beta-carbolinyl;-   and all other variables are as defined in the second class of the    invention;-   or a pharmaceutically acceptable salt thereof.

In an aspect of the first sub-class, A is selected from the groupconsisting of indolyl, phenothiazinyl, benzimidazolyl, phthalazinyl, anddihydroimidazothiazolyl.

In another aspect of the first sub-class, A is indolyl.

Exemplary compounds of the invention include compounds selected from thegroup consisting of

-   2-({[(8-hydroxy-1,6-naphthyridin-7-yl)carbonyl]amino}methyl)-1H-benzimidazole;-   8-hydroxy-N-[2-(1H-indol-3-yl)ethyl]-1,6-naphthyridine-7-carboxamide;-   N-{2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethyl}-8-hydroxy-1,6-naphthyridine-7carboxamide;-   8-hydroxy-N-[(2-oxo-2,3-dihydro-1H-indol-3-yl)methyl]-1,6-naphthyridine-7carboxamide;-   8-hydroxy-N-[2-(10H-phenothiazin-10-yl)ethyl]-1,6-naphthyridine-7-carboxamide;-   8-hydroxy-N-[2-(2-methyl-1-phenyl-1H-indol-3-yl)ethyl]-1,6-naphthyridine-7carboxamide;-   8-hydroxy-N-(1H-indol-6-ylmethyl)-1,6-naphthyridine-7-carboxamide;-   8-hydroxy-N-(1H-indol-2-ylmethyl)-1,6-naphthyridine-7-carboxamide;-   8-hydroxy-N-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]-1,6-naphthyridine-7carboxamide;-   tert-butyl    3-({[(8-hydroxy-1,6-naphthyridin-7-yl)carbonyl]amino}methyl)-1H-indole-1-carboxylate;-   8-hydroxy-N-(1H-indol-3-ylmethyl)-1,6-naphthyridine-7-carboxamide;-   6-({[(8-hydroxy-1,6-naphthyridin-7-yl)carbonyl]amino}methyl)-2,3-dihydroimidazo[2,1-b[]1,3]thiazole;-   8-hydroxy-N-(4-pyridinylmethyl)[1,6]naphthyridine-7-carboxamide;-   8-hydroxy-N-(2-pyridinylmethyl)[1,6]naphthyridine-7-carboxamide;-   and pharmaceutically acceptable salts thereof.

Other embodiments of the invention include compounds of Formula (I),(II), (III), or (IV), wherein each variable is independently as definedin any one of the preceding embodiments, classes, sub-classes oraspects.

Other embodiments of the present invention include the following:

(a) A pharmaceutical composition comprising a compound of Formula (I)and a pharmaceutically acceptable carrier.

(b) The pharmaceutical composition of (a), further comprising at leastone antiviral selected from the group consisting of HIV proteaseinhibitors, non-nucleoside HIV reverse transcriptase inhibitors, andnucleoside HIV reverse transcriptase inhibitors.

(c) A method of inhibiting HIV integrase in a subject in need thereofwhich comprises administering to the subject a therapeutically effectiveamount of a compound of Formula (I).

(d) A method of preventing or treating infection by HIV in a subject inneed thereof which comprises administering to the subject atherapeutically effective amount of a compound of Formula (I).

(e) The method of (d), wherein the compound of Formula (I) isadministered in combination with a therapeutically effective amount ofat least one antiviral selected from the group consisting of HIVprotease inhibitors, non-nucleoside HIV reverse transcriptaseinhibitors, and nucleoside HIV reverse transcriptase inhibitors.

(f) A method of preventing, treating or delaying the onset of AIDS in asubject in need thereof which comprises administering to the subject atherapeutically effective amount of a compound of Formula (I).

(g) The method of (f), wherein the compound is administered incombination with a therapeutically effective amount of at least oneantiviral selected from the group consisting of HIV protease inhibitors,non-nucleoside HIV reverse transcriptase inhibitors, and nucleoside HIVreverse transcriptase inhibitors

(h) A method of inhibiting HIV integrase in a subject in need thereofwhich comprises administering to the subject a therapeutically effectiveamount of the composition of (a) or (b).

(i) A method of preventing or treating infection by HIV in a subject inneed thereof which comprises administering to the subject atherapeutically effective amount of the composition of (a) or (b).

(j) A method of preventing, treating or delaying the onset of AIDS in asubject in need thereof which comprises administering to the subject atherapeutically effective amount of the composition of (a) or (b).

Still other embodiments of the present invention include the following:

(k) A pharmaceutical composition which comprises the product prepared bycombining (e.g., mixing) an effective amount of a compound of Formula(I) and a pharmaceutically acceptable carrier.

(l) A combination useful for inhibiting HIV integrase, for treating orpreventing infection by HIV, or for preventing, treating or delaying theonset of AIDS, which is a therapeutically effective amount of a compoundof Formula (I) and a therapeutically effective amount of an HIVinfection/AIDS treatment agent selected from the group consisting ofHIV/AIDS antiviral agents, immunomodulators, and anti-infective agents.

(m) The combination of (l), wherein the HIV infection/AIDS treatmentagent is an antiviral selected from the group consisting of HIV proteaseinhibitors, non-nucleoside HIV reverse transcriptase inhibitors andnucleoside HIV reverse transcriptase inhibitors.

Additional embodiments of the invention include the pharmaceuticalcompositions and methods set forth in (a)-(j) above and the compositionsand combinations set forth in (k)-(m), wherein the compound employedtherein is a compound of one of the embodiments, classes, sub-classes,or aspects of compounds described above. In all of these embodiments,the compound may optionally be used in the form of a pharmaceuticallyacceptable salt.

The present invention also includes use of a compound of Formula (I-A):

or a pharmaceutically acceptable salt thereof, for inhibiting HIVintegrase, for preventing or treating infection by HIV or forpreventing, treating or delaying the onset of AIDS in a subject in needthereof; wherein A, R¹, R², R³, R⁴, R⁵, L, Q¹, Q², Q³, and Q⁴ are eachindependently as originally defined above or as defined in any of theforegoing embodiments, classes, sub-classes, or aspects. In one aspect,the compound of Formula (I-A) is N-[2-(1H-Indol-3-yl)ethyl]8-hydroxyquinoline-7-carboxamide; or a pharmaceutically acceptable saltthereof.

The present invention also include embodiments for compounds of Formula(I-A) analogous to embodiments (a)-(m) for compounds of Formula (I).

As used herein, the term “C₁₋₆ alkyl” (or “C₁-C₆ alkyl”) means linear orbranched chain alkyl groups having from 1 to 6 carbon atoms and includesall of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-,sec- and t-butyl, n- and isopropyl, ethyl and methyl. “C₁₋₄ alkyl” meansn-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.

The term “C₀” as employed in expressions such as “C₀₋₆ alkyl” means adirect covalent bond.

The term “C₂₋₅ alkenyl” (or “C₂-C₅ alkenyl”) means linear or branchedchain alkenyl groups having from 2 to 5 carbon atoms and includes all ofthe pentenyl isomers as well as 1-butenyl, 2-butenyl, 3-butenyl,isobutenyl, 1-propenyl, 2-propenyl, and ethenyl (or vinyl). Similarterms such as “C₂₋₃ alkenyl” have an analogous meaning.

The term “C₂₋₅ alkynyl” (or “C₂-C₅ alkynyl”) means linear or branchedchain alkynyl groups having from 2 to 5 carbon atoms and includes all ofthe pentynyl isomers as well as 1-butynyl, 2-butynyl, 3-butynyl,1-propynyl, 2-propynyl, and ethynyl (or acetylenyl). Similar terms suchas “C₂₋₃ alkynyl” have an analogous meaning.

The term “C₃₋₇ cycloalkyl” (or “C₃-C₇ cycloalkyl”) means a cyclic ringof an alkane having three to seven total carbon atoms (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl). Theterm “C₃₋₆ cycloalkyl” refers to a cyclic ring selected fromcyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Terms such as“C₃-C₅ cycloalkyl” have an analogous meaning.

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine andiodine (alternatively, fluoro, chloro, bromo, and iodo).

The term “thio” (also referred to as “thioxo”) means divalent sulfur;i.e., ═S.

The term “C₁₋₆ haloalkyl” (which may alternatively be referred to as“C₁-C₆ haloalkyl” or “halogenated C₁-C₆ alkyl”) means a C₁ to C₆ linearor branched alkyl group as defined above with one or more halogensubstituents. The term “C₁₋₄ haloalkyl” has an analogous meaning.

The term “C₁₋₆ fluoroalkyl” (which may alternatively be referred to as“C₁-C₆ fluoroalkyl” or “fluorinated C₁-C₆ alkyl”) means a C₁ to C₆linear or branched alkyl group as defined above with one or morefluorine substituents. The term “C₁₋₄ fluoroalkyl” (or “C₁-C₄fluoroalkyl” or “fluorinated C₁-C₄ alkyl”) has an analogous meaning.Representative examples of suitable fluoroalkyls include the series(CH₂)₀₋₄CF₃ (i.e., trifluoromethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoro-n-propyl, etc.), 1-fluoroethyl, 2-fluoroethyl,2,2-difluoroethyl, 3,3,3-trifluoroisopropyl,1,1,1,3,3,3-hexafluoroisopropyl, and perfluorohexyl.

The term “carbocycle” (and variations thereof such as “carbocyclic” or“carbocyclyl”) as used herein broadly refers to a C₃ to C₈ monocyclic,saturated or unsaturated ring or a C₇ to C₁₂ bicyclic ring system inwhich the rings are independent or fused and in which each ring issaturated or unsaturated. The carbocycle may be attached at any carbonatom which results in a stable compound. The fused bicyclic carbocyclesare a subset of the carbocycles; i.e., the term “fused bicycliccarbocycle” generally refers to a C₇ to C₁₀ bicyclic ring system inwhich each ring is saturated or unsaturated and two adjacent carbonatoms are shared by each of the rings in the ring system. A subset ofthe fused bicyclic carbocycles are the fused bicyclic carbocycles inwhich one ring is a benzene ring and the other ring is saturated orunsaturated, with attachment via any carbon atom that results in astable compound. Representative examples of this subset include thefollowing:

As used herein, the term “fused carbocyclic ring system” refers to acarbocycle as defined above which is fused to a phenyl ring.Representative examples include:

The term “aryl” refers to aromatic mono- and poly-carbocyclic ringsystems, wherein the individual carbocyclic rings in the polyringsystems may be fused or attached to each other via a single bond.Suitable aryl groups include, but are not limited to, phenyl, naphthyl,and biphenylenyl.

The term “heterocycle” (and variations thereof such as “heterocyclic” or“heterocyclyl”) broadly refers to a 4- to 8-membered monocyclic ring, 7-to 12-membered bicyclic ring system, or an 11 to 16-membered tricyclicling system, any ring of which is saturated or unsaturated, and whichconsists of carbon atoms and one or more heteroatoms selected from N, Oand S, and wherein the nitrogen and sulfur heteroatoms may optionally beoxidized, and the nitrogen heteroatom may optionally be quaternized. Theheterocyclic ring may be attached at any heteroatom or carbon atom,provided that attachment results in the creation of a stable structure.When the heterocyclic ring has substituents, it is understood that thesubstituents may be attached to any atom in the ring, whether aheteroatom or a carbon atom, provided that a stable chemical structureresults. Representative examples of heterocyclics include piperidinyl,piperazinyl, azepinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl,imidazolyl, imidazolidinyl, triazolyl, tetrazolyl, imidazolinyl, pyridyl(or pyridinyl), pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl,thiazolyl, thiazolidinyl, isothiazolyl, quinoxazolinyl,isothiazolidinyl, quinolinyl, isoquinolinyl, benzimidazolyl,thiadazolyl, benzopyranyl, benzothiazolyl, benzoazolyl, furyl (orfuranyl), tetrahydrofuryl (or tetrahydrofuranyl), tetrahydropuranyl,thienyl (alternatively thiophenyl), benzothiophenyl, oxadiazolyl, andbenzo-1,3-dioxacyclopentyl (alternatively, 1,3-benzodioxolyl).Representative examples of heterocyclics also include tetrahydrothienyl,tetrahydrodioxothienyl, thiadiazinanyl, dioxothiadiazinanyl,thiazinanyl, dioxothiazinanyl, dioxothiazolidinyl, andisodioxothiazolidinyl. Representative examples of heterocyclics alsoinclude the following bicyclics: indolyl, benzotriazolyl,imidazo[4,5-b]pyridinyl, dihydroimidazo[4,5-b]pyridinyl,pyrazolo[4,3-c]pyridinyl, dihydropyrazolo[4,3-c]pyridinyl,tetrahydropyrazolo[4,3c]pyridinyl, pyrrolo[1,2-a]pyrazinyl,dihydropyrrolo[1,2-a]pyrazinyl, tetrahydropyrrolo[1,2-a]pyrazinyl,octahydropyrrolo[1,2-a]pyrazinyl, isoindolyl, indazolyl, indolinyl,isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, andisochromanyl. Additional representative examples of bicyclics includethe following: phthalazinyl, purinyl, 1,6-naphthyridinyl,1,8-napthyridinyl, dihydroindolyl, dihydroisoindolyl,tetrahydroquinolyl, tetrahydroisoquinolyl, imidazo[1,2-a]pyrimidinyl,2,3-dihydroimidazo[2,1-b][1,3]thiazolyl, benzazepinyl,dihydrobenazepinyl, benzodiazepinyl, dihydrobenzodiazepinyl, andtetrahydrobenzodiazepinyl. Representative examples of heterocyclics alsoinclude the following tricyclics: phenothiazinyl, carbazolyl,beta-carbolinyl, tetrahydro-beta-carbolinyl, acridinyl, phenazinyl, andphenoxazinyl.

Representative examples of heterocyclics also include the followingsaturated monocyclics: hexahydropyrimidinyl, thiazinanyl (e.g.,1,2-thiazinanyl, alternatively named tetrahydro-1,2-thiazinyl),thiazepanyl (e.g., 1,4-thiazepanyl, alternatively namedhexahydro-1,4-thiazepinyl), azepanyl (alternatively hexahydroazepinyl),thiadiazepanyl (e.g., 1,2,5-thiadiazepanyl), dithiazepanyl (e.g.,1,5,2,-dithiazepanyl), diazepanyl (e.g., 1,4-diazepanyl), andthiadiazinanyl (e.g., 1,2,6-thiadiazinanyl).

A representative unsaturated heterocycle is

wherein p is an integer from zero to 4 and R^(a) is as defined above,and wherein each ring carbon is optionally and independently substitutedwith —C₁₋₄ alkyl.

Representative examples of heterocyclics also include the followingbicyclics: hexahydropyrazolo[4,3-c]pyridinyl (e.g.,3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3c]pyridinyl), hexahydropurinyl(e.g., 2,3,4,5,6,7-hexahydro-1H-purinyl),hexahydrooxazolo[3,4a]pyrazinyl, and1,2,3,4-tetrahydro-1,8-naphthyridinyl.

Fused ring heterocycles form a subset of the heterocycles as definedabove; e.g., the term “fused bicyclic heterocycle” refers to aheteroatom-containing bicyclic ring system as defined in the precedingparagraph in which two adjacent atoms are shared by both rings. A subsetof the fused bicyclic heterocycles is the fused bicyclic heterocyclecontaining carbon atoms and one or more heteroatoms selected fromnitrogen, oxygen and sulfur, wherein one ring is a benzene ring and theother is a saturated or unsaturated heteroatom-containing ring.Representative examples of this subset include, but are not limited to,the following:

The term “heteromonocycle” (and variations thereof such as“heteromonocyclyl” or “heteromonocyclic”) refers to a 4- to 8-memberedmonocyclic ring which is saturated or unsaturated, and which consists ofcarbon atoms and one or more heteroatoms selected from N, O and S, andwherein the nitrogen and sulfur heteroatoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized. Theheterocyclic ring may be attached at any heteroatom or carbon atom,provided that attachment results in the creation of a stable structure.Representative examples of monoheterocycles are disclosed above.

Heteroaromatics form another subset of the heterocycles as definedabove; i.e., the term “heteroaromatic” (alternatively, “heteroaryl”)generally refers to a heterocycle as defined above in which the ringsystem (whether mono- or poly-cyclic) is an aromatic ring system. Theterm “heteroaromatic ring” refers to a monocyclic heterocycle as definedabove which is an aromatic heterocycle. Representative examples ofheteroaromatics include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl,pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl,thiazolyl, isothiazolyl, and thiadiazolyl.

Unless expressly set forth to the contrary, an “unsaturated” ring is apartially or fully unsaturated ring. For example, an “unsaturatedmonocyclic C₆ carbocycle” refers to cyclohexene, cyclohexadine, andbenzene.

The present invention includes pharmaceutical compositions useful forinhibiting HIV integrase, comprising an effective amount of a compoundof this invention, and a pharmaceutically acceptable carrier.Pharmaceutical compositions useful for treating infection by HIV, or fortreating AIDS or ARC, are also encompassed by the present invention, aswell as a method of inhibiting HIV integrase, and a method of treatinginfection by HIV, or of treating AIDS or ARC. Additionally, the presentinvention is directed to a pharmaceutical composition comprising atherapeutically effective amount of a compound of the present inventionin combination with a therapeutically effective amount of an agent fortreating HIV infection or AIDS selected from:

(1) an antiviral agent useful for treating or preventing HIV infectionor for treating AIDS (also referred to herein as an HIV/AIDS antiviralagent),

(2) an anti-infective agent, and

(3) an immunomodulator.

The present invention also includes a compound of the present inventionfor use in (a) inhibiting HIV integrase, (b) preventing or treatinginfection by HIV, or (c) preventing, treating or delaying the onset ofAIDS or ARC. The present invention also includes the use of a compoundof the present invention as described above as a medicament for (a)inhibiting HIV integrase, (b) preventing or treating infection by HIV,or (c) preventing, treating or delaying the onset of AIDS or ARC. Thepresent invention further includes the use of any of the HIV integraseinhibiting compounds of the present invention as described above incombination with one or more HIV/AIDS treatment agents selected from anHIV/AIDS antiviral agent, an anti-infective agent, and animmunomodulator as a medicament for (a) inhibiting HIV integrase, (b)preventing or treating infection by HIV, or (c) preventing, treating ordelaying the onset of AIDS or ARC, said medicament comprising aneffective amount of the HIV integrase inhibitor compound and aneffective amount of the one or more treatment agents.

The present invention also includes the use of a compound of the presentinvention as described above in the preparation of a medicament for (a)inhibiting HIV integrase, (b) preventing or treating infection by HIV,or (c) preventing, treating or delaying the onset of AIDS or ARC.

The present invention further includes the use of any of the HIVintegrase inhibiting compounds of the present invention as describedabove in combination with one or more HIV/AIDS treatment agents selectedfrom an HIV/AIDS antiviral agent, an anti-infective agent, and animmunomodulator for the manufacture of a medicament for (a) inhibitingHIV integrase, (b) preventing or treating infection by HIV, or (c)preventing, treating or delaying the onset of AIDS or ARC, saidmedicament comprising an effective amount of the HIV integrase inhibitorcompound and an effective amount of the one or more treatment agents.

The compounds of the present invention may have asymmetric centers andmay occur, except when specifically noted, as mixtures of stereoisomersor as individual diastereomers, or enantiomers, with all isomeric formsbeing included in the present invention.

When any variable (e.g., R^(a), R^(b), R^(c), R^(k), etc.) occurs morethan one time in any constituent or in Formula I or in any other formuladepicting and describing compounds of the invention, its definition oneach occurrence is independent of its definition at every otheroccurrence. Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “substituted” (e.g., as in “phenyl ring, unsubstituted orsubstituted with from 1 to 5 substituents . . . ”) includes mono- andpoly-substitution by a named substituent to the extent such single andmultiple substitution is chemically allowed. For example, a carbocycleor heterocycle substituted with more than one substituent can havemultiple substituents on the same ring atom to the extent it ischemically permitted. A ring sulfur atom in a saturated heterocycle can,for example, typically be substituted with 1 (—S(═O)—) or 2 oxo groups(—SO₂—).

The compounds of the present inventions are useful in the inhibition ofHIV integrase, the prevention or treatment of infection by humanimmunodeficiency virus (HIV) and the treatment of consequentpathological conditions such as AIDS. Treating AIDS or preventing ortreating infection by HIV is defined as including, but not limited to,treating a wide range of states of HIV infection: AIDS, ARC (AIDSrelated complex), both symptomatic and asymptomatic, and actual orpotential exposure to HIV. For example, the compounds of this inventionare useful in treating infection by HIV after suspected past exposure toHIV by e.g., blood transfusion, exchange of body fluids, bites,accidental needle stick, or exposure to patient blood during surgery.

The compounds of this invention are useful in the preparation andexecution of screening assays for antiviral compounds. For example, thecompounds of this invention are useful for isolating enzyme mutants,which are excellent screening tools for more powerful antiviralcompounds. Furthermore, the compounds of this invention are useful inestablishing or determining the binding site of other antivirals to HIVintegrase, e.g., by competitive inhibition. Thus the compounds of thisinvention are commercial products to be sold for these purposes.

The present invention also provides for the use of a compound of Formula(I) or (I-A) to make a pharmaceutical composition useful for inhibitingHIV integrase and in the treatment of AIDS or ARC.

The compounds of the present invention may be administered in the formof pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” is intended to include all acceptable salts such asacetate, lactobionate, benzenesulfonate, laurate, benzoate, malate,bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate,borate, methylbromide, bromide, methylnitrate, calcium edetate,methylsulfate, carnsylate, mucate, carbonate, napsylate, chloride,nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt,dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate(embonate), estolate, palmitate, esylate, pantothenate, fumarate,phosphate/diphosphate, gluceptate, polygalacturonate, gluconate,salicylate, glutamate, stearate, glycollylarsanilate, sulfate,hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide,tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide,tosylate, isothionate, triethiodide, lactate, panoate, valerate, and thelike which can be used as a dosage form for modifying the solubility orhydrolysis characteristics or can be used in sustained release orpro-drug formulations. Depending on the particular functionality of thecompound of the present invention, pharmaceutically acceptable salts ofthe compounds of this invention include those formed from cations suchas sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, andfrom bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine,arginine, omithine, choline, N,N′-dibenzylethylene-diamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine,diethylamine, piperazine, tris(hydroxymethyl)aminomethane, andtetramethylammonium hydroxide. These salts may be prepared by standardprocedures, e.g. by reacting a free acid with a suitable organic orinorganic base. Where a basic group is present, such as amino, an acidicsalt, i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like,can be used as the dosage form.

Also, in the case of an acid (—COOH) or alcohol group being present,pharmaceutically acceptable esters can be employed, e.g. acetate,maleate, pivaloyloxymethyl, and the like, and those esters known in theart for modifying solubility or hydrolysis characteristics for use assustained release or prodrug formulations.

For these purposes, the compounds of the present invention may beadministered orally, parenterally (including subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques), by inhalation spray, or rectally, in dosage unitformulations containing conventional non-toxicpharmaceutically-acceptable carriers, adjuvants and vehicles.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention each meanproviding the compound or a prodrug of the compound to the individual inneed of treatment. When a compound of the invention or prodrug thereofis provided in combination with one or more other active agents (e.g.,antiviral agents useful for treating HIV infection or AIDS),“administration” and its variants are each understood to includeconcurrent and sequential provision of the compound or prodrug thereofand other agents.

Thus, in accordance with the present invention there is further provideda method of treating and a pharmaceutical composition for treating HIVinfection and AIDS. The treatment involves administering to a subject inneed of such treatment a pharmaceutical composition comprising apharmaceutical carrier and a therapeutically-effective amount of acompound of the present invention.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The term “subject,” (alternatively referred to herein as “patient”.) asused herein refers to an animal, preferably a mammal, most preferably ahuman, who has been the object of treatment, observation or experiment.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease being treated.

These pharmaceutical compositions may be in the form oforally-administrable suspensions or tablets or capsules, nasal sprays,sterile injectible preparations, for example, as sterile injectibleaqueous or oleagenous suspensions or suppositories.

When administered orally as a suspension, these compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may contain microcrystalline cellulose for impartingbulk, alginic acid or sodium alginate as a suspending agent,methylcellulose as a viscosity enhancer, and sweeteners/flavoring agentsknown in the art. As immediate release tablets, these compositions maycontain microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants known in the art.

When administered by nasal aerosol or inhalation, these compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other solubilizing or dispersingagents known in the art.

The injectible solutions or suspensions may be formulated according toknown art, using suitable non-toxic, parenterally-acceptable diluents orsolvents, such as mannitol, 1,3-butanediol, water, Ringer's solution orisotonic sodium chloride solution, or suitable dispersing or wetting andsuspending agents, such as sterile, bland, fixed oils, includingsynthetic mono- or diglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, thesecompositions may be prepared by mixing the drug with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

The compounds of this invention can be administered orally to humans ina dosage range of 0.1 to 1000 mg/kg body weight in divided doses. Onepreferred dosage range is 0.1 to 200 mg/kg body weight orally in divideddoses. Another preferred dosage range is 0.5 to 100 mg/kg body weightorally in divided doses. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0.20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0,600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. It will be understood, however, that the specific doselevel and frequency of dosage for any particular patient may be variedand will depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular condition, and the host undergoing therapy.

The present invention is also directed to combinations of the HIVintegrase inhibitor compounds with one or more agents useful in thetreatment of HIV infection or AIDS. For example, the compounds of thisinvention may be effectively administered, whether at periods ofpre-exposure and/or post-exposure, in combination with effective amountsof the HIV/AIDS antivirals, immunomodulators, antiinfectives, orvaccines useful for treating HIV infection or AIDS, such as those in thefollowing Table.

Drug Name Manufacturer Indication ANTIVIRALS Amprenavir Glaxo WellcomeHIV infection, AIDS, 141 W94 ARC GW 141 (protease inhibitor) AbacavirGlaxo Welcome HIV infection, AIDS, GW 1592 ARC 1592U89 (reversetranscriptase inhibitor) Acemannan Carrington Labs ARC (Irving, TX)Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in combinationwith AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 TanoxBiosystems HIV infection, AIDS, ARC Adefovir dipivoxil Gilead SciencesHIV infection AL-721 Ethigen ARC, PGL, HIV positive, (Los Angeles, CA)AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV, incombination w/Retrovir Ansamycin Adria Laboratories ARC LM 427 (Dublin,OH) Erbamont (Stamford, CT) Antibody which Advanced Biotherapy AIDS, ARCneutralizes pH Concepts labile alpha aberrant (Rockville, MD) InterferonAR177 Aronex Pharm HIV infection, AIDS, ARC beta-fluoro-ddA Nat'l CancerInstitute AIDS-associated diseases BMS-232623 Bristol-Myers Squibb/ HIVinfection, AIDS, (CGP-73547) Novartis ARC (protease inhibitor)BMS-234475 Bristol-Myers Squibb/ HIV infection, AIDS, (CGP-61755)Novartis ARC (protease inhibitor) CI-1012 Warner-Lambert HIV-1 infectionCidofovir Gilead Science CMV retinitis, herpes, papillomavirus Curdlansulfate AJI Pharma U.S.A. HIV infection Cytomegalovirus immune MedImmuneCMV retinitis globin Cytovene Syntex sight threatening CMV Ganciclovirperipheral CMV retinitis Delaviridine Pharmacia-Upjohn HIV infection,AIDS, ARC (protease inhibitor) Dextran Sulfate Ueno Fine Chem. AIDS,ARC, HIV Ind. Ltd. (Osaka, Japan) positive asymptomatic ddC Hoffman-LaRoche HIV infection, AIDS, ARC Dideoxycytidine ddI Bristol-Myers SquibbHIV infection, AIDS, ARC; Dideoxyinosine combination with AZT/d4Tmozenavir AVID HIV infection, AIDS, (DMP-450) (Camden, NJ) ARC (proteaseinhibitor) EL10 Elan Corp, PLC HIV infection (Gainesville, GA) EfavirenzDuPont (SUSTIVA ®), HIV infection, AIDS, (DMP 266) Merck (STOCRIN ®) ARC(−) 6-Chloro-4(S)- (non-nucleoside RT cyclopropylethynyl- inhibitor)4(S)-trifluoro-methyl- 1,4-dihydro-2H-3,1- benzoxazin-2-one, FamciclovirSmith Kline herpes zoster, herpes simplex FTC Emory University HIVinfection, AIDS, ARC (reverse transcriptase inhibitor) GS 840 Gilead HIVinfection, AIDS, ARC (reverse transcriptase inhibitor) HBY097 HoechstMarion Roussel HIV infection, AIDS, ARC (non-nucleoside reversetranscriptase inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARCRecombinant Human Triton Biosciences AIDS, Kaposi's sarcoma, InterferonBeta (Almeda, CA) ARC Interferon alfa-n3 Interferon Sciences ARC, AIDSIndinavir Merck HIV infection, AIDS, ARC, asymptomatic HIV positive,also in combination with AZT/ddI/ddC Compound A Merck HIV infection,AIDS, ARC, asymptomatic HIV positive ISIS 2922 ISIS Pharmaceuticals CMVretinitis KNI-272 Nat'l Cancer Institute HIV-assoc. diseases Lamivudine,3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptaseinhibitor); also with AZT Lobucavir Bristol-Myers Squibb CMV infectionNelfinavir Agouron HIV infection, AIDS, Pharmaceuticals ARC (proteaseinhibitor) Nevirapine Boeheringer HIV infection, AIDS, Ingleheim ARC(protease inhibitor) Novapren Novaferon Labs, Inc. HIV inhibitor (Akron,OH) Peptide T Peninsula Labs AIDS Octapeptide (Belmont, CA) SequenceTrisodium Astra Pharm. CMV retinitis, HIV infection, PhosphonoformateProducts, Inc other CMV infections PNU-140690 Pharmacia Upjohn HIVinfection, AIDS, ARC (protease inhibitor) Probucol Vyrex HIV infection,AIDS RBC-CD4 Sheffield Med. Tech HIV infection, AIDS, (Houston TX) ARCRitonavir Abbott HIV infection, AIDS, (ABT-538) ARC (protease inhibitor)Saquinavir Hoffmann-LaRoche HIV infection, AIDS, ARC (proteaseinhibitor) Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, ARCDidehydrodeoxy- thymidine Valaciclovir Glaxo Wellcome genital HSV & CMVinfections Virazole Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa,CA) positive, LAS, ARC VX-478 Vertex HIV infection, AIDS, ARCZalcitabine Hoffmann-La Roche HIV infection, AIDS, ARC, with AZTZidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi'ssarcoma in combination with other therapies (reverse transcriptaseinhibitor) ABT-378; Lopinavir Abbott HIV infection, AIDS, ARC (proteaseinhibitor) ABT-378/r; contains Abbott HIV infection, AIDS, ARC lopinavirand ritonavir; (protease inhibitor) Kaletra JE2147/AG1776 Agouron HIVinfection, AIDS, ARC (protease inhibitor) T-20 Trimeris HIV infection,AIDS, ARC (fusion inhibitor) T-1249 Trimeris HIV infection, AIDS, ARC(fusion inhibitor) atazanavir Bristol-Myers-Squibb HIV infection, AIDS,ARC (BMS 232632) (protease inhibitor) PRO 542 Progenics HIV infection,AIDS, ARC (attachment inhibitor) PRO 140 Progenics HIV infection, AIDS,ARC (CCR5 co-receptor inhibitor) TAK-779 Takeda HIV infection, AIDS, ARC(injectable CCR5 receptor antagonist) DPC 681 & DPC 684 DuPont HIVinfection, AIDS, ARC (protease inhibitors) DPC 961 & DPC 083 DuPont HIVinfection AIDS, ARC (nonnucleoside reverse transcriptase inhibitors)Trizivir (contains abacavir, GlaxoSmithKline HIV infection, AIDS, ARClamivudine, and (reverse transcriptase zidovudine) inhibitors)tipranavir (PNU-140690) Boehringer Ingelheim HIV infection, AIDS, ARC(purchased from (protease inhibitor) Pharmacia & Upjohn) tenofovirdisoproxil Gilead HIV infection, AIDS, ARC fumarate (reversetranscriptase inhibitor) TMC-120 & TMC-125 Tibotec HIV infections, AIDS,ARC (non-nucleoside reverse transcriptase inhibitors) TMC-126 TibotecHIV infection, AIDS, ARC (protease inhibitor) IMMUNO-MODULATORS AS-101Wyeth-Ayerst AIDS Bropirimine Pharmacia Upjohn advanced AIDS AcemannanCarrington Labs, Inc. AIDS, ARC (Irving, TX) CL246,738 American CyanamidAIDS, Kaposi's sarcoma Lederle Labs EL10 Elan Corp, PLC HIV infection(Gainesville, GA) FP-21399 Fuki ImmunoPharm blocks HIV fusion with CD4+cells Gamma Interferon Genentech ARC, in combination w/TNF (tumornecrosis factor) Granulocyte Genetics Institute AIDS Macrophage ColonySandoz Stimulating Factor Granulocyte Hoeschst-Roussel AIDS MacrophageColony Immunex Stimulating Factor Granulocyte Schering-Plough AIDS,combination w/AZT Macrophage Colony Stimulating Factor HIV Core ParticleRorer seropositive HIV Immunostimulant IL-2 Cetus AIDS, in combinationInterleukin-2 w/AZT IL-2 Hoffman-La Roche AIDS, ARC, HIV, inInterleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase inCD4 cell Interleukin-2 counts (aldeslukin) Immune Globulin CutterBiological pediatric AIDS, in Intravenous (Berkeley, CA) combinationw/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma,ARC, PGL IMREG-2 Imreg AIDS, Kaposi's sarcoma, (New Orleans, LA) ARC,PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio CarbamateAlpha-2 Schering Plough Kaposi's sarcoma w/AZT, Interferon AIDSMethionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PECiba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide Granulocyte AmgenAIDS, in combination Colony Stimulating w/AZT Factor Remune ImmuneResponse Corp. immunotherapeutic rCD4 Genentech AIDS, ARC RecombinantSoluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS,ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma,AIDS, Alfa 2a ARC, in combination w/AZT SK&F106528 Smith Kline HIVinfection Soluble T4 Thymopentin Immunobiology HIV infection ResearchInstitute Tumor Necrosis Genentech ARC, in combination Factor; TNFw/gamma Interferon etanercept Immunex Corp rheumatoid arthritis(Enbrel ®) infliximab Centocor (Remicade ®) rheumatoid arthritis andCrohn's disease ANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCPPrimaquine Fluconazole Pfizer cryptococcal meningitis, candidiasisPastille Squibb Corp. prevention of oral candidiasis Nystatin PastilleOrnidyl Merrell Dow PCP Eflornithine Pentamidine LyphoMed PCP treatmentIsethionate (IM & IV) (Rosemont, IL) Trimethoprim antibacterialTrimethoprim/sulfa antibacterial Piritrexim Burroughs Wellcome PCPtreatment Pentamidine Fisons Corporation PCP prophylaxis isethionate forinhalation Spiramycin Rhone-Poulenc cryptosporidia diarrheaIntraconazole- Janssen Pharm. histoplasmosis; cryptococcal R51211meningitis Trimetrexate Warner-Lambert PCP OTHER Daunorubicin NeXstar,Sequus Karposi's sarcoma Recombinant Human Ortho Pharm. Corp. severeanemia assoc. with Erythropoietin AZT therapy Recombinant Human SeronoAIDS-related wasting, Growth Hormone cachexia Leukotriene B4 Receptor —HIV infection Antagonist Megestrol Acetate Bristol-Myers Squibbtreatment of anorexia assoc. w/AIDS Soluble CD4 Protein and — HIVinfection Derivatives Testosterone Alza, Smith Kline AIDS-relatedwasting Total Enteral Norwich Eaton diarrhea and malabsorption,Nutrition Pharmaceuticals related to AIDS

It will be understood that the scope of combinations of the compounds ofthis invention with HIV/AIDS antivirals, immunomodulators,anti-infectives or vaccines is not limited to the list in the aboveTable, but includes in principle any combination with any pharmaceuticalcomposition useful for the treatment of HIV infection or AIDS. Whenemployed in combination with the compounds of the invention, theHIV/AIDS antivirals and other agents are typically employed in theirconventional dosage ranges and regimens as reported in the art,including the dosages described in the Physicians' Desk Reference,54^(th) edition, Medical Economics Company, 2000. The dosage ranges fora compound of the invention in these combinations are the same as thoseset forth above just before the Table.

Preferred combinations are simultaneous or sequential treatments of acompound of the present invention and an inhibitor of HIV proteaseand/or a non-nucleoside inhibitor of HIV reverse transcriptase. Anoptional fourth component in the combination is a nucleoside inhibitorof HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferredinhibitor of HIV protease is the sulfate salt of indinavir, which isN-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-N′-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Still another preferredprotease inhibitor is Compound A, which isN-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(2-benzo[b]furanylmethyl)-2(S)-N′-(t-butylcarboxamido)piperazinyl))pentaneamide,preferably administered as the sulfate salt. Compound A can be preparedas described in U.S. Pat. No. 5,646,148. Preferred non-nucleosideinhibitors of HIV reverse transcriptase include efavirenz. Thepreparation of ddC, ddI and AZT are also described in EPO 0,484,071.These combinations may have unexpected effects on limiting the spreadand degree of infection of HIV. Preferred combinations include acompound of the present invention with the following (1) indinavir withefavirenz, and, optionally, AZ and/or 3TC and/or ddI and/or ddC; (2)indinavir, and any of AZT and/or ddI and/or ddC and/or 3TC, inparticular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/orzidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5)zidovudine and lamivudine.

Another preferred combination is a compound of the present inventionwith indinavir and Compound A and optionally with one or more ofefavirenz, AZT, 3TC, ddI and ddC. In one embodiment of this combination,the weight ratio of indinavir to Compound A is from about 1:1 to about1:2, wherein the amount of indinavir employed is in the range of fromabout 200 to about 1000 mg. Indinavir and Compound A can be administeredconcurrently or sequentially in either order from one to three times perday.

In such combinations the compound of the present invention and otheractive agents may be administered together or separately. In addition,the administration of one agent may be prior to, concurrent to, orsubsequent to the administration of other agent(s).

Abbreviations used in the instant specification, particularly theSchemes and Examples, are as follows:

-   DEAD=diethylazodicarboxylate-   DMF=N,N-dimethylformamide-   DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone-   DMSO=dimethylsulfoxide-   EDC=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-   ES MS=electrospray mass spectrometry-   Et=ethyl-   FAB HRMS=fast atom bombardment high resolution mass spectroscopy-   FAB MS=fast atom bombardment mass spectroscopy-   HOBt=1-hydroxy benzotriazole hydrate-   HPLC=high performance liquid chromatography-   i-Pr=isopropyl-   Me=methyl-   MsCl=methanesulfonyl chloride (or mesyl chloride)-   NBS=N-bromosuccinimide-   NIS=N-iodosuccinimide-   NMR=nuclear magnetic resonance-   Ph=phenyl-   PMBCI=p-methoxybenzyl chloride-   rt and RT=room temperature-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran

The compounds of the present invention can be readily prepared accordingto the following reaction schemes and examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art, but are not mentioned in greater detail.Furthermore, other methods for preparing compounds of the invention willbe readily apparent to the person of ordinary skill in the art in lightof the following reaction schemes and examples. Unless otherwiseindicated, all variables are as defined above.

The compounds of the present invention can be prepared by the couplingof suitable (poly)azanaphthenyl carboxylic acids (or acid derivativessuch as acid halides or esters) with the appropriate amines, asrepresented by the following general scheme:

Methods for coupling carboxylic acids with amines to form carboxamidesare well known in the art. Suitable methods are described, for example,in Jerry March, Advanced Organic Chemistry, 3rd edition, John Wiley &Sons, 1985, pp. 370-376. Amines of formula 1-1 can be prepared using themethods described in Richard Larock, Comprehensive OrganicTransformations, VCH Publishers Inc, 1989, pp 385-438, or routinevariations thereof. Azanaphthenyl and polyazanaphthenyl carboxylic acidsof formula 1-2 can be prepared using methods described in Ochiai et al.,Chem. Ber. 1937, 70: 2018, 2023; Albert et al., J. Chem. Soc. 1952,4985, 4991; and Barlin et al., Aust. J. Chem. 1990, 43: 1175-1181; orroutine variations thereof. Schemes 2-16 below illustrate and expandupon the chemistry portrayed in Scheme 1.

In Scheme 2, following the procedure set forth in Ornstein et al., J.Med. Chem. 1989, 32: 827-833, a cyclic anhydride such as quinolinicanhydride (i.e., Z¹=Z²=Z³=CH in 2-1) can be opened with isopropanol toprovide mono acid 2-2, which can be converted to the corresponding acylchloride 2-3 (e.g., by refluxing thionyl chloride). Acyl chloride 2-3can then be reduced (e.g., with NaBH₄ or LiBH₄) to the correspondingalcohol 2-4, which can be converted to the corresponding bromide throughthe action of bromine in the presence of triphenylphosphine. Alkylationof the bromide with the sodium anion of phenylsulfonamide 2-5 in a polaraprotic solvent like DMF can provide sulfonamide 2-6, which can betreated with a base (e.g., alkali metal alkoxide such as sodiummethoxide) to provide the bicyclic ester 2-7 via a Dieckmanncyclization.

Saponification of the ester (e.g., with aqueous NaOH at reflux) willafford the acid 2-8. The acid 2-8 can be activated with triphosgene andcoupled with a variety of amines to provide the compounds of theinvention 2-9.

The starting anhydrides of formula 2-1 can be prepared via methodsdescribed in Philips et al., Justus Liebigs Ann. Chem. 1895, 288: 2535;Bernthsen et al., Chem. Ber. 1887; 20: 1209; Bly et al., J. Org. Chem.1964, 29: 2128-2135; and Krapcho et al., J. Heterocycl. Chem. 1993, 30:1597-1606; or routine variations thereof.

Scheme 3 depicts an alternative synthesis in which alcohol 2-4 canundergo the Mitsunobu reaction with the phenylsulfonamide of glycinemethyl ester to provide 3-1. The sulfonamide 3-1 can again be elaboratedto provide the acid 2-8, which can be coupled with a variety of aminesusing standard reagents to provide the compounds of the invention 2-9.

Scheme 3A depicts (for a napthyridine core) a variation of the synthesisshown in Scheme 3, wherein the acid 3A-2 is reacted with ethylchloroformate to form the mixed anhydride 3A-3, which is reduced toalcohol 3A-4.

Halogen substituted compounds of the present invention can be preparedas shown in Scheme 4. The acid chloride 2-3 can be reacted with glycinemethyl ester to provide the amide 4-1. Dieckmann cyclization of theester 4-1 with a sodium alkoxide base in an alcoholic solvent likemethanol will provide phenol 4-2., which can be reacted with phosphorousoxychloride, followed by methanolysis of the intermediate phosphonateesters to provide 4-3. The ester bond of 4-3 can react selectively withsuitable amines (e.g., 1-(1H-indol-2-yl)methanamine is depicted inScheme 4) to provide the corresponding halogenated derivative 4-4.

The preparation of compounds that feature additional substituents can beachieved as shown in Scheme 5. Oxidation of the alcohol 2-4 withmanganese dioxide in an inert solvent such as methylene chloride willprovide aldehyde 5-1. The addition of Grignard reagents (such as phenylmagnesium bromide) to aldehyde moiety 5-1 can occur regioselectively toprovide the alcohol 5-2, which can then be elaborated to the compoundsof the invention 5-6.

A further synthetic route to prepare compounds that are the subject ofthe invention is shown in Scheme 6. This methodology allows access tonaphthyridine derivatives that are substituted at the 2, 3, 4 and 5positions. Briefly, a 2-substituted 5-hydroxypyridine derivative 6-1 canbe treated with bromine to undergo bromination at the 6 position toafford 6-2, which can be converted to the methoxypyridine 6-3 and thenoxidized to the corresponding N-oxide 6-4. The N-oxide can be nitratedto provide 6-5. Reduction of 6-5 with iron in the presence of ammoniumchloride can provide the aniline 6-6, which can be reacted with analpha,beta-unsaturated aldehyde or ketone in the presence of an acidcatalyst like sulfuric acid to provide 6-7 via an annulation. Thebromide 6-7 can be elaborated to the amide 6-9 via a sequence ofcarbonylation and amidation reactions.

2-Substituted 5-hydroxypyridine derivatives of formula 6-1 can beprepared via methods described in Sorm et al., Collect. Czech. Chem.Commun. 1949, 14: 331,342; and Saksena et al., Tetrahedron Lett. 1993,34: 3267-3270: or routine variations thereof.

Compounds of the invention that comprise an amino substituent at the 5position can be prepared in the manner set forth in Schemes 7 and 8.Bromination of the phenol 7-1 occurs regioselectively upon treatmentwith NBS in an inert solvent like methylene chloride to afford 7-2.Reaction of this bromide with an amine at elevated temperatures in thepresence of a polar solvent such as DMPU affords compounds of theinvention 7-3. Similar reaction of the bromide 7-2 (Scheme 8) with adiamine such as ethylene diamine in DMF as solvent will afford theformylated derivative 8-1 in addition to the expected diaminoethanederivative.

Preparation of aryl and heteroaryl derivatives via palladium crosscoupling of the chloride 9-1 and the requisite boronic acids aredepicted in Scheme 9.

(Hetero)aryloxy, (hetero)arylamino, and (heteroaryl)thioxy derivatives10-2, 11-2, and 12-2 respectively can be prepared as shown in Schemes 10to 12, which exemplify the procedure for the naphthyridine core. Thecorresponding sulfone derivatives 12-2 can be obtained by oxidation ofthe sulfides 12-1 with either ozone or 3-chloroperbenzoic acid as shownin Scheme 12.

Preparation of compounds of the invention substituted with an acetylenecan be prepared according to Scheme 13, which exemplifies the procedurefor the naphthyridine core. Following protection of the iodide 13-2 asits benzoate 13-3, the acetylenic group (for example propynol) can beappended by employing a suitable palladium catalyst in the presence ofcopper iodide. Aminolysis of the ester 13-4 will afford the amide 13-5with concomitant deprotection of the benzoate ester. Alternately theester 13-4 can be converted to the corresponding amine and sulfonederivatives as shown in Schemes 14 and 15. Scheme 16 shows that thepreparation of the nitrile derivative 16-2 can be achieved via apalladium catalyzed cyanation of the iodide 13-4.

In the processes for preparing compounds of the present invention setforth in the foregoing schemes, functional groups in various moietiesand substituents may be sensitive or reactive under the reactionconditions employed and/or in the presence of the reagents employed.Such sensitivity/reactivity can interfere with the progress of thedesired reaction to reduce the yield of the desired product, or possiblyeven preclude its formation. Accordingly, it may be necessary ordesirable to protect sensitive or reactive groups on any of themolecules concerned. Protection can be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973 and in T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known in the art. Alternatively theinterfering group can be introduced into the molecule subsequent to thereaction step of concern. For example, if one or more of thesubstituents R¹, R², R³, and R⁴ in compound 1-1 can interfere with thecoupling reaction between compounds 1-1 and 1-2 of Scheme 1, thesubstituent can be incorporated into the molecule in a post-couplingstep to afford Compound I.

The following examples serve only to illustrate the invention and itspractice. The examples are not to be construed as limitations on thescope or spirit of the invention.

EXAMPLE 12-({[(8-hydroxy-1,6-naphthyridin-7-yl)carbonyl]amino}methyl)-1H-benzimidazole

Step 1: Preparation of3-{[Methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-pyridine-2-carboxylicacid isopropyl ester

Isopropyl 3-(hydroxymethyl)pyridine-2-carboxylate (prepared inaccordance with P. Ornstein et. al. J. Med. Chem. 1989, 32, 827) (200 g,1.02 mol), methyl N-[(4-methylphenyl)sulfonyl]glycinate (249 g, 1.02mol), and triphenylphosphine (403 g, 1.5 mol) were dissolved in dry THF(3000 mls) and cooled to zero degrees under N2. Thediethylazodicarboxylate (DEAD) (267.6 g, 1.5 mol) was dissolved in dryTHF (250 mls) and placed in a 500 ml addition funnel. The DEAD was addeddropwise over 1 hour. The ice bath was removed and the reaction wasallowed to warm slowly to RT. After 2 hours, the reaction was checked byHPLC (above conditions) and some glycinate remained. More startingreagents were added and the reaction was left to stir at RT. After 30min, the reaction was checked again and saw a very small amount of theglycinate remaining. Concentrated reaction down to a reddish-orange oilthat was carried onto the next step.

Step 2: Preparation of Methyl 8-hydroxy-1,6-naphthyridine-7-carboxylate

3-{[Methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-pyridine-2-carboxylicacid isopropyl ester (1.02 mol) was dissolved in dry methanol (4000 ml)and cooled to zero degrees under nitrogen. Then via addition funnel,sodium methoxide (137.8 g, 2.5 mol) was added slowly to avoid anyexotherm. The reaction was stirred at zero degrees, and checked by HPLCafter 1.5 hours and was found to be completed. The solvent was removedin vacuo to obtain a reddish-orange oil, which was partitioned betweenwater (1L) and ethyl acetate (1L). The organic layer was back extractedwith saturated sodium bicarbonate solution. The pH of the aqueous layerwas adjusted to 7, and the layer was maintained at this pH whileextracting with methylene chloride. The organic layer was dried withNa2SO4, filtered, and the solvent was removed in vacuo to obtain a tansolid. The solid was dissolved in hot ethyl acetate, and the solutionwas filtered while hot to filter out any insoluble material. The productprecipitated upon cooling. The precipitate was then filtered and driedin a vacuum oven. The filtrate was recrystallized by concentrating thefiltrate and redissolving the resulting solid in a minimal amount ofmethylene chloride. Sufficient ethyl acetate was added to turn thesolution slightly cloudy, after which the solution was boiled to reducethe volume, cooled, and the resulting crystals were filtered out anddried in a vacuum oven.

1H NMR (CDCl3, 500 MHz) δ 11.794 (5H, s), 9.2 (1H, dd, J=1.7 and 6.1Hz), 8.8 (1H, s), 8.3 (1H, dd, J=1.5 and 9.7 Hz), 7.7 (1H, dd, J=4.2 and12.4 Hz), 4.1 (3H, s) ppm. ES MS exact mass calculated for C₁₀H₈N₂O₃204.1869 (MH+), found 205.1.

Step 3: Preparation of 8-hydroxy-1,6-naphthyridine-7-carboxylic acid

To a slurry of methyl 8-hydroxy-1,6-naphthyridine-7-carboxylate fromExample 1, Step 2 (1.50 g, 7.35 mmol) in methanol (45 ml) was addedlithium hydroxide (22.0 ml of a 1M aq. solution, 22.0 mmol) and thereaction was heated at 100° C. for 7 hrs. Upon cooling to roomtemperature, hydrochloric acid (22.0 ml of a 1M aq. solution, 22.0 mmol)was added and the reaction stirred for 16 hrs. The mixture wasconcentrated to a volume of 50 ml and neutralized with dilute NaHCO₃(pH=7) The resulting precipitate was collected by filtration and washedwith water and dried in vacuo to afford the title compound.

FAB MS calcd for C₉H₆N₂O₃ 191 (MH⁺), found 191. ¹H NMR (D₆DMSO, 400 MHz)δ 9.20 (1H, m), 8.72 (1H, s), 8.58 (1H, m), 7.80 (1H, dd, J=8.3 and 4.2Hz) ppm.

Step 4: Preparation of2-({[(8-hydroxy-1,6-naphthyridin-7-yl)carbonyl]amino}methyl)-1H-benzimidazol-1-iumTrifluoroacetate

Triphosgene (0.556 g, 1.87 mmol) was added over 20 mins to a solution ofthe acid from Step 1. (0.89 g, 4.68 mmol) and diisopropylethylamine 3.26ml, 18.7 mmol) in DMF (22 ml) at 0° C. The dark solution was allowed towarm to room temperature and stirred a further 1 hr.2-(ammoniomethyl)-1H-benzimidazol-1-ium dichloride hydrate (25.0 mg,1.05 mmol) was treated with a portion of the above solution (0.58 ml,0.07 mmol) and the resulting mixture was stirred at room temperature for16 hrs. The solution was treated with TFA (0.025 ml) and purified bypreparative HPLC. (Gilson semi preparative HPLC system and a YMCCombiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) (available fromWaters) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min)to afford the trifluoroacetate salt of the title compound afterlyophilization.

¹H NMR (d₆DMSO, 400 MHz) δ 10.03 (1H, m), 9.21 (1H, d, J=4.2 Hz), 9.00(1H, s), 8.66 (1H, d, J=8.3 Hz), 7.85 (1H, dd, J=8.3 and 4.2 Hz),7.80-7.65 (2H, m), 7.60-7.40 (2H, m), 5.05 (2H, d, J=4.9 Hz) ppm. FAB MScalcd for C₁₇H₁₃N₅O₂ 320 (MH⁺), found 320. FAB HRMS exact mass calcd forC₁₇H₁₃N₅O₂ 320.1142 (MH⁺), found 320.1145.

EXAMPLE 28-hydroxy-N-[2-(1H-indol-3-yl)ethyl]-1,6-naphthyridine-7-carboxamide

The title compound was prepared using the procedure described in Example1, Step 4 replacing 2-(ammoniomethyl)-1H-benzimidazol-1-ium dichloridehydrate with 2-(1H-indol-3-yl)ethanamine.

¹H NMR (d₆DMSO, 400 MHz) δ 10.85 (1H, s), 9.40 (1H, m), 9.16 (1H, dd,J=4.3 and 1.6 Hz), 8.90 (1H, s), 8.61 (1H, dd, J=8.2 and 1.6 Hz), 7.83(1H, dd, J=8.2 and 4.2 Hz), 7.62 (1H, d, J=8.1 Hz), 7.34 (1H, d, J=7.8Hz), 7.23 (1H, s), 7.07 (1H, t, J=7.5 Hz), 7.00 (1H, t, J=6.5 Hz), 3.66(2H, m), 3.03 (2H, t, J=7.7 Hz) ppm. FAB MS calcd for C₁₉H₁₆N₄O₂ 333(MH⁺), found 333.

EXAMPLE 3N-{2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethyl}-8-hydroxy-1,6-naphthyridine-7-carboxamide

The title compound was prepared using the procedure described in Example1, Step 4 replacing 2-(ammoniomethyl)-1H-benzimidazol-1-ium dichloridehydrate with 3-(2-aminoethyl)-2-(3,4-dimethoxyphenylindole).

¹H NMR (d₆DMSO, 400 MHz) δ 11.1 (1H, s), 9.55 (1H, m), 9.17 (1H, d,J=4.2 Hz), 8.89 (1H, s), 8.61 (1H, d, J=8.2 Hz), 7.84 (1H, dd, J=8.2 and4.2 Hz), 7.74 (1H, d, J=8.1 Hz), 7.36 (1H, d, J=7.9 Hz), 7.26 (1H, d,J=8.2 Hz), 7.22 (1H, s), 7.10 (1H, t, J=7.6 Hz), 7.10-7.00 (2H, m), 3.73(3H, s), 3.70-3.40 (2H, m), 3.18 (2H, t, J=7.9 Hz) ppm. FAB MS calcd forC₂₇H₂₄N₄O₄ 469 (MH⁺), found 469. FAB HRMS exact mass calcd forC₂₇H₂₄N₄O₄ 469.1870317 (MH⁺), found 469.1871720.

EXAMPLE 48-hydroxy-N-[(2-oxo-2,3-dihydro-1H-indol-3-yl)methyl]-1,6-naphthyridine-7-carboxamide

The title compound was prepared using the procedure described in Example1, Step 4 replacing 2-(ammoniomethyl)-1H-benzimidazol-1-ium dichloridehydrate with 3-(aminomethyl)-1,3-dihydro-2H-indol-2-one.

¹H NMR (d₆DMSO, 400 MHz) δ 10.4 (1H, s), 9.54 (1H, m), 9.18 (1H, d,J=4.3 Hz), 8.92 (1H, s), 8.63 (1H, d, J=8.3 Hz), 7.84 (1H, dd, J=8.3 and4.3 Hz), 7.22 (2H, t, J=7.4 Hz), 6.96 (2H, t, J=7.4 Hz), 5.48 (1H, m),3.03 (1H, dd, J=16.0 and 10.3 Hz), 2.75 (1H, dd, J=16.0 and 6.0 Hz) ppm.FAB MS calcd for C₁₈H₁₄N₄O₃ 335 (MH⁺), found 335. FAB HRMS exact masscalcd for C18H₁₄N₄O₃ 335.1139 (MH⁺), found 335.1143

EXAMPLE 58-hydroxy-N-[2-(10H-phenothiazin-10-yl)ethyl]-1,6-naphthyridine-7-carboxamide

The title compound was prepared using the procedure described in Example1, Step 4 replacing 2-(ammoniomethyl)-1H-benzimidazol-1-ium dichloridehydrate with 2-(10H-phenothiazin-10-yl)ethanamine.

¹H NMR (d₆DMSO, 400 MHz) δ 9.55 (1H, t, J=6.2 Hz), 9.18 (1H, dd, J=4.2and 1.6 Hz), 8.93 (1H, s), 8.62 (1H, dd, J=8.4 and 1.6 Hz), 7.84 (1H,dd, J=8.4 and 4.2 Hz), 7.65-7.40 (4H, m), 7.15 (2H, m), 6.96 (2H, m),4.09 (2H, m), 3.74 (2H, m) ppm. FAB MS calcd for C₂₃H₁₈N₄O₂S 415 (MH⁺),found 415. FAB HRMS exact mass calcd for C₂₃H₁₈N₄O₂S 415.1223 (MH⁺),found 415.1224.

EXAMPLE 68-hydroxy-N-[2-(2-methyl-1-phenyl-1H-indol-3-yl)ethyl]-1,6-naphthyridine-7-carboxamide

The title compound was prepared using the procedure described in Example1, Step 4 replacing 2-(ammoniomethyl)-1H-benzimidazol-1-ium dichloridehydrate with 2-(2-methyl-1-phenyl-1H-indol-3-yl)ethanamine.

¹H NMR (d₆DMSO, 400 MHz) δ 9.47 (1H, t, J=6.0 Hz), 9.17 (1H, dd, J=4.2and 1.6 Hz), 8.92 (1H, s), 8.62 (1H, dd, J=8.4 and 1.6 Hz), 7.84 (1H,dd, J=8.4 and 4.2 Hz), 7.67 (1H, d, J=6.9 Hz), 7.59 (2H, t, J=7.8 Hz),7.48 (1H, t, J=7.2 Hz), 7.41 (2H, d, J=7.2 Hz), 7.20-6.95 (3H, m),3.80-3.20 (2H, m), 3.08 (2H, t, J=7.3 Hz) 2.24 (3H, s) ppm. FAB MS calcdfor C₂₆H₂₂N₄O₂ 423 (MH⁺), found 423. FAB HRMS exact mass calcd forC₂₆H₂₂N₄O₂ 423.1804 (MH⁺), found 423.1804.

EXAMPLE 78-hydroxy-N-(1H-indol-6-ylmethyl)-1,6-naphthyridine-7-carboxamide

The title compound was prepared using the procedure described in Example1, Step 4 replacing 2-(ammoniomethyl)-1H-benzimidazol-1-ium dichloridehydrate with 1-(1H-indol-6-yl)methanamine.

¹HNMR (d₆DMSO, 400 MHz) δ 11.00 (1H, s), 9.79 (1H, m), 9.17 (1H, d,J=4.2 Hz), 8.91 (1H, s), 8.61 (1H, d, J=8.3 Hz), 7.83 (1H, dd, J=8.3 and4.2 Hz), 7.49 (1H, d, J=8.3 Hz), 7.42 (1H, s), 7.30 (1H, s), 7.06 (1H,d, J=8.1 Hz), 6.38 (1H, s), 4.64 (2H, d, J=6.3 Hz) ppm. FAB MS calcd forC₁₈H₁₄N₄O₂ 319 (MH⁺), found 319.

EXAMPLE 88-hydroxy-N-(1H-indol-2-ylmethyl)-1,6-naphthyridine-7-carboxamide

The title compound was prepared using the procedure described in Example1, Step 4 replacing 2-(ammoniomethyl)-1H-benzimidazol-1-ium dichloridehydrate with 1-(1H-indol-2-yl)methanamine.

¹H NMR (d₆DMSO, 400 MHz) δ 11.00 (1H, s), 9.73 (1H, m), 9.17 (1H, m),8.94 (1H, s), 8.61 (1H, d, J=8.2 Hz), 7.84 (1H, dd, J=8.2 and 4.2 Hz),7.46 (1H, d, 7.9 Hz), 7.36 (1H, d, J=8.1 Hz), 7.04 (1H, t, J=8.0 Hz),6.95 (1H, t, J=7.4 Hz), 6.33 (1H, s), 4.73 (2H, d, J=6.2 Hz) ppm. FAB MScalcd for C₁₈H₁₄N₄O₂ 319 (MH⁺), found 319.

EXAMPLE 98-hydroxy-N-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]-1,6-naphthyridine-7-carboxamide

The title compound was prepared using the procedure described in Example1, Step 4 replacing 2-(ammoniomethyl)-1H-benzimidazol-1-ium dichloridehydrate with 4-(aminomethyl)phthalazin-1(2H)-one.

¹H NMR (d₆DMSO, 400 MHz) δ 9.68 (1H, m), 9.18 (1H, dd, J=1.5 and 4.2Hz), 8.94 (1H, s), 8.62 (1H, dd, J=8.2 and 1.5 Hz), 8.30 (1H, d, J=7.5Hz), 8.17 (1H, d, J=9.0 Hz), 7.99 (1H, t, J=7.7 Hz), 7.84 (1H, dd, J=7.2and 4.0 Hz), 4.95 (2H, m) ppm. FAB MS calcd for C₁₈H₁₃N₅O₃ 319 (MH⁺),found 348.

EXAMPLE 10 tert-butyl3-({[(8-hydroxy-1,6-naphthyridin-7-yl)carbonyl]amino}methyl)-1H-indole-1-carboxylate

The title compound was prepared using the procedure described in Example1, Step 4 replacing 2-(ammoniomethyl)-1H-benzimidazol-1-ium dichloridehydrate with tert-butyl 3-(aminomethyl)-1H-indole-1-carboxylate.

¹H NMR (d₆DMSO, 400 MHz) δ 9.70 (1H, m), 9.16 (1H, dd, J=1.7 and 4.3Hz), 8.90 (1H, s), 8.60 (1H, dd, J=8.2 and 1.7 Hz), 8.05 (1H, d, J=8.3Hz), 7.85 (1H, d, J=9.5 Hz), 7.82 (1H, dd, =4.2 and 8.3 Hz), 7.66 (1H,s), 7.33 (1H, t, J=8.4 Hz), 7.20 (1H, t, J=7.3 Hz), 4.69 (2H, m) ppm.FAB MS calcd for C₂₃H₂₂N₄O₄ 319 (MH⁺), found 419.

EXAMPLE 118-hydroxy-N-(1H-indol-3-ylmethyl)-1,6-naphthyridine-7-carboxamide

A solution of tert-butyl3-({[(8-hydroxy-1,6-naphthyridin-7-yl)carbonyl]amino}methyl)-1H-indole-1-carboxylatefrom Example 10 (12.0 mg, 0.0029 mmol) in CH₂Cl₂ (1 ml) was treated withtrifluroacetic acid (TFA) (1 ml) and resulting mixture was stirred atroom temperature for 1 hr and then the solvent was evaporated in vacuo.The resulting material was dissolved in DMSO (1 ml) and aged for 24 hrsat room temperature. This solution was purified by preparative HPLC.(Gilson semi preparative HPLC system and a YMC Combiprep Pro Column(50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water(0.1% TFA) at 15 min/min) to afford the title compound afterlyophilization.

¹H NMR (d₆DMSO, 400 MHz) δ 10.98 (1H, s), 9.49 (1H, m) 9.15 (1H, d,J=4.2 Hz), 8.85 (1H, s), 8.58 (1H, d, J=8.3 Hz), 7.81 (1H, dd, J=8.3 and4.2 Hz), 7.75 (1H, dd, J=7.7 Hz), 7.40-7.30 (2H, m), 7.08 (1H, t, J=7.0Hz), 7.00 (1H, t, J=7.0 Hz), 4.71 (2H, d, J=6.0 Hz) ppm. FAB MS calcdfor C₁₈H₁₄N₄O₂ 319 (MH⁺), found 319.

EXAMPLE 126-({[(8-hydroxy-1,6-naphthyridin-7-yl)carbonyl]amino}methyl)-2,3-dihydroimidazo[2,1-b][1,3]thiazole

The title compound was prepared as the imidazothiazol-4-iumtrifluoroacetate salt using the procedure described in Example 1, Step 4replacing 2-(ammoniomethyl)-1H-benzimidazol-1-ium dichloride hydratewith 1-(2,3-dihydroimidazo[2,1-b][1,3]thiazol-6-yl)methanamine.

¹H NMR (d₆DMSO, 400 MHz) δ 9.67 (1H, t, J=6.9 Hz), 9.17 (1H, dd, J=4.2and 1.6 Hz), 8.92 (1H, s), 8.62 (1H, dd, J=8.2 and 1.6 Hz), 7.85 (1H,dd, J=8.2 and 4.2 Hz), 7.47 (1H, s), 4.50 (2H, d, J=6.0 Hz) 4.32 (2H, t,J=7.5 Hz), 4.02 (2H, t, J=7.5 Hz) ppm. FAB MS calcd for C₁₅H₁₃N₅O₂S 328(MH⁺), found 328. FAB HRMS exact mass calcd for C₁₅H₁₃N₅O₂S 328.0863(MH⁺), found 328.085.

EXAMPLE 138-hydroxy-N-(4-pyridinylmethyl)[1,6]naphthyridine-7-carboxamide

To a solution of methyl 8-hydroxy-1,6-naphthyridine-7-carboxylate fromExample 1, Step 2 (0.05 g, 0.245 mmol) in dry toluene (3 mL) was added1-pyridin-4-ylmethanamine (0.029 g, 0.270 mmol) and the mixture washeated to reflux for 16 hours. The solution was reduced to a smallervolume and refluxed for 4 additional hours. The solvent was removedunder reduced pressure and the residue redissolved in DMF and filteredand the solution solution was purified by preparative HPLC (Gilsonsemipreparative HPLC system and a YMC Combiprep Column (50×20 mm I.D.,C18, S-5 uM, 120 A) eluting with 5-95% acetonitrile/water (0.1% TFA) at15 ml/min) to afford the title compound after lyophilization.

¹H NMR (d₆DMSO, 400 MHz) δ 10.07 (1H, m), 9.18 (1H, m), 8.97 (1H, d,J=1.47 Hz), 8.75 (2H, dd, J=5.0 Hz), 8.64 (1H, dd, J=8.3 Hz), 7.86 (1H,m), 7.77 (2H, d, J=5.1 Hz), 4.76 (2H, d, J=4.6 Hz) ppm. FAB MS calcd forC₁₅H₁₂N₄O₂ 281 (H⁺), found 281. FAB HRMS exact mass calcd for C₁₅H₁₂N₄O₂281.1033 (MH⁺), found 281.1032. Anal. Calcd for C₁₅H₁₂N₄O₂.1.25TFA.1.00H₂O: C, 47.68; H, 3.49; N, 12.71. Found: C, 47.68; H, 3.70; N,12.03.

EXAMPLE 148-hydroxy-N-(2-pyridinylmethyl)[1,6]naphthyridine-7-carboxamide

To a solution of methyl 8-hydroxy-1,6-naphthyridine-7-carboxylate fromExample 1, Step 2 (0.05 g, 0.245 mmol) in dry toluene (3 mL) was added1-pyridin-2-ylmethanamine (0.029 g, 0.270 mmol) and the mixture washeated to reflux for 16 hours. The solution was reduced to a smallervolume and refluxed for 4 additional hours. The solvent was removedunder reduced pressure and the residue redissolved in DMF and filteredand the solution was purified by preparative HPLC (Gilsonsemipreparative HPLC system and a YMC Combiprep Column (50×20 mm I.D.,C18, S-5 uM, 120 A) eluting with 5-95% acetonitrile/water (0.1% TFA) at15 ml/min) to afford the title compound after lyophilization.

¹H NMR (d₆DMSO, 400 MHz) δ 9.88 (1H, m), 9.18 (1H, m), 8.96 (1H, d,J=1.1 Hz), 8.63 (2H, m), 7.96 (1H, dd, J=7.6 Hz), 7.86 (1H, m), 7.55(1H, d, J=7.6 Hz), 7.46 (1H, dd, J=5.3 Hz), 4.76 (2H, d, J=4.6 Hz) ppm.FAB MS calcd for C₁₅H₁₂N₄O₂ 281 (H⁺), found 281. FAB HRMS exact masscalcd for C₁₅H₁₂N₄O₂ 281.1033 (MH⁺), found 281.1040. Anal. Calcd forC₁₅H₁₂N₄O₂.1.45 TFA.0.1H₂O: C, 48.05; H, 3.08; N, 12.52. Found: C,48.04; H, 3.29; N, 12.17.

EXAMPLE 15 N-[2-(1H-Indol-3-yl)ethyl]8-hydroxyquinoline-7-carboxamide

A mixture of 8-hydroxyquinoline-7-carboxylic acid (0.23 g, 1.25 mmol),2-(1H-Indol-3-yl)ethylamine (0.20 g, 1.25 mmol), 1-hydroxybenzotriazole(0.18 g, 1.37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.26 g, 1.37 mmol), and triethylamine (0.7 mL, 4.99 mmol)in DMF (12 mL) was stirred at room temp overnight. The reaction mixturewas concentrated under vacuum. The residue was dissolved in DMSO andsubjected to HPLC purification on C-18 stationary phase eluted withwater/acetonitrile/TFA mobile phase. Collection and lyophilization ofappropriate fractions provide the title compound as yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H), 9.08 (br s, 1H), 8.92 (br s,1H), 8.42 (br d, 1H), 8.02 (d, 1H), 7.70 (br m, 1H), 7.61 (d, 1H), 7.46(d, 1H), 7.34 (d, 1H), 7.22 (d, 1H), 7.07 (t, 11), 7.00 (t, 1H), 3.67(q, 2H), 3.02 (t, 2H).

EXAMPLE 16 Oral Composition

As a specific embodiment of an oral composition of a compound of thisinvention, 50 mg of compound of Example 1 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size 0 hard gelatin capsule.

EXAMPLE 17 HIV Integrase Assay: Strand Transfer Catalyzed by RecombinantIntegrase

Assays for the strand transfer activity of integrase were conducted inaccordance with Wolfe, A. L. et al., J. Virol. 1996, 70: 1424-1432, forrecombinant integrase, except that: (i) the assays used preassembledintegrase strand transfer complexes; (ii) the strand transfer reactionwas performed in the presence of inhibitor in 2.5 mM MgCl₂ using 0.5 to5 nM of a 3′FITC labeled target DNA substrate (SEQ. ID. NO: 1 and SEQ.ID. NO: 2)

5′ TGA CCA AGG GCT AAT TCA CT fitc 3′ 3′ fitc ACT GGT TCC CGA TTA AGT GA5′;and (iii) strand transfer products were detected using an alkalinephosphatase conjugated anti-FITC antibody and a chemiluminescentalkaline phosphatase substrate. Representative compounds tested in theintegrase assay demonstrated IC₅₀'s of less than about 100 micromolar.

Further description on conducting the assay using preassembled complexesis found in Hazuda et al., J. Virol. 1997, 71: 7005-7011; Hazuda et al.,Drug Design and Discovery 1997, 15: 17-24; and Hazuda et al., Science2000, 287: 646-650.

EXAMPLE 18 Assay for Inhibition of HIV Replication

Assays for the inhibition of acute HIV infection of T-lymphoid cellswere conducted in accordance with Vacca, J. P. et al., (1994), Proc.Natl. Acad. Sci. USA 91, 4096. Representative compounds tested in thepresent assay demonstrated IC₉₅'s of less than about 20 micromolar.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, thepractice of the invention encompasses all of the usual variations,adaptations and/or modifications that come within the scope of thefollowing claims.

1. A compound of Formula (IV):

wherein A is (i) a monocyclic heterocycle selected from the groupconsisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyrazidinyl, oxazolyl, isooxazolyl,thiazolyl, isothiazolyl, pyrrolidinyl, pyrazolidinyl imidazolinyl,piperidinyl, piperazinyl, thiazolidinyl, isothiazolidinyl, andmorpholinyl; (ii) a fused bicyclic heterocycle selected from the groupconsisting of indolyl, isoindolyl, phthalazinyl, purinyl, quinoxalinyl,quinazolinyl, cinnolinyl, 1,6-naphthyridinyl, 1,8-napthyridinyl,benzimidazolyl, quinolinyl, isoquinolinyl, indazolyl, dihydroindolyl,dihydroisoindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl,imidazo[1,2-a]pyrimidinyl, 2,3-dihydroimidazo[2,1-b][1,3]thiazolyl,benzazepinyl, dihydrobenazepinyl, benzodiazepinyl,dihydrobenzodiazepinyl, tetrahydrobenzodiazepinyl, and benzothiazolyl;or (iii) a fused tricyclic heterocycle selected from the groupconsisting of phenothiazinyl, carbazolyl, beta-carbolinyl,tetrahydro-beta-carbolinyl, acridinyl, phenazinyl, and phenoxazinyl; Q²is (1) —H, (2) methyl, (3) ethyl, (4) CF₃, (5) methoxy, (6) ethoxy (7)—OCF₃ (8) halo selected from —F, —Cl and —Br, (9) —CN, (10) —CH₂OH, (11)—CH₂OCH₃ (12) —(CH₂)₀₋₂CO₂CH₃, (13) —SR^(a), (14) —N(R^(a))₂, (15)—SO₂R^(a), (16) —C≡C—CH₂OR^(a), (17) —N(R^(a))—(CH₂)₁₋₃SR^(a), (18)—N(R^(a))—(CH₂)₁₋₃OR^(a), (19) —N(R^(a))—(CH₂)₁₋₃N(R^(a))₂, (20)—N(R^(a))—(CH₂)₁₋₃N(R^(a))—C(R^(a))═O, (21) —R^(k), (22) —(CH₂)₁₋₄R^(k),(23) —C≡C—CH₂R^(k), (24) —O—R^(k), (25) —S—R^(k), (26) —SO₂—R^(k), (27)—N(R^(c))—R^(k), (28) —N(R^(c))—(CH₂)₁₋₄H substituted with one or twoR^(k) groups, (29) —N(R^(c))—(CH₂)₁₋₄OR^(k), (30) —C(═O)N—(CH₂)₁₋₄R^(k),(31) —C≡C—CH₂SR^(a), or (32) —C≡C—CH₂SO₂R^(a); each of R¹ and R² isindependently: (1) —H, (2) methyl, (3) ethyl, (4) CF₃, (5) methoxy, (6)ethoxy (7) —OCF₃ (8) halo selected from —F, —Cl and —Br, (9) —CN, (10)—CH₂OR^(a), (11) —CO₂R^(a), (12) —SR^(a), (13) —N(R^(a))₂, (14)—(CH₂)₁₋₃N(R^(a))₂, (15) —SO₂R^(a), (16) —(CH₂)₁₋₂N(R^(a))—C(R^(a))═O,(17) —R^(k), (18) —(CH₂)₁₋₃H substituted with 1 or 2 R^(k) groups, (19)—O—R^(k), or (20) —O—(CH₂)₁₋₃R^(k); each R^(a) is independently —H or—C₁₋₄ alkyl; each R^(c) is independently —H, —C₁₋₄ alkyl, or—(CH₂)₁₋₃N(R^(a))₂; each R^(k) is independently: (1) phenyl which isunsubstituted or substituted with from 1 to 4 substituents independentlyselected from: (a) halogen selected from —F, —Cl, and —Br, (b) methyl,(c) —CF₃, (d) methoxy, (e) —OCF₃, (f) phenyl, (g) —S—CH₃, (h) —CN, (i)—OH, (j) phenyloxy, unsubstituted or substituted with from 1 to 3substituents independently selected from: (i) halogen selected from —F,—Cl, and —Br, (ii) methyl, (iii) —CF₃, and (iv) —OH, (k) —N(R^(a))₂, (l)—(CH₂)₁₋₃N(R^(a))₂, (m) —R^(t), (n) —(CH₂)₀₋₃C(═O)N(R^(a))₂, and (o)—(CH₂)₀₋₃C(═O)R_(a); (2) —C₃₋₆ cycloalkyl, unsubstituted or substitutedwith from 1 to 3 substituents independently selected from: (a) halogenselected from —F, —Cl, and —Br, (b) methyl, (c) —CF₃, (d) methoxy, (e)—OCF₃, (f) —CN, (g) phenyl, and (h) —OH; (3) a 5- or 6-memberedheteroaromatic ring selected from thienyl, pyridyl, imidazolyl,pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl,pyrazinyl, pyirimidinyl, triazolyl, tetrazolyl, furanyl, andpyridazinyl, wherein the heteroaromatic ring is unsubstituted orsubstituted on nitrogen or carbon with 1 or 2 substituents independentlyselected from: (a) halogen selected from —F, —Cl, and —Br, (b) methyl,(c) —CF₃, (d) methoxy, (e) —OCF₃, (f) phenyl, (g) —S—C₁₋₆ alkyl, (h)—CN, (i) —OH, (j) phenyloxy, unsubstituted or substituted with from 1 to3 substituents independently selected from: (i) halogen selected from—F, —Cl, and —Br, (ii) methyl, (iii) —CF₃, and (iv) —OH, (k) —N(R^(a))₂,(l) —C₁₋₆ alkyl-N(R^(a))₂, (m) —R^(t), (n) oxo, (o)—(CH₂)₀₋₃C(═O)N(R^(a))₂, and (p) —(CH₂)₀₋₃C(═O)R^(a); (4) a 5- or6-membered saturated heterocyclic ring selected from piperidinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl,oxazolidinyl, isooxazolidinyl, pyrrolidinyl, imidazolidinyl,piperazinyl, tetrahydrofuranyl, and pyrazolidinyl, wherein theheterocyclic ring is unsubstituted or substituted with 1 or 2substituents independently selected from: (a) halogen selected from —F,—Cl, and—Br, (b) methyl, (c) —CF₃, (d) methoxy, (e) —OCF₃, (f) —CN, (g)═O, (h) phenyl, (i) benzyl, (j) phenylethyl, (k) —OH, (l)—(CH₂)₀₋₃C(═O)N(R^(a))₂, (m) —(CH₂)₀₋₃C(═O)R^(a), (o)N(R^(a))—C(═O)OR^(a), (p) (CH₂)₁₋₃N(R^(a))—C(═O)R^(a), (q) N(R^(a))₂,(r) (CH₂)₁₋₃N(R^(a))₂, (s) —(CH₂)₀₋₃C(═O)R^(t), (t) —R^(t), (u)—N(R^(a))R^(t), and (v) —(CH₂)₁₋₃R^(t); and (5) an 8- to 10-memberedheterobicyclic ring selected from indolyl, benzotriazolyl,benzoimidazolyl, imidazo[4,5-b]pyridinyl,dihydroimidazo[4,5-b]pyridinyl, pyrazolo[4,3-c]pyridinyl,dihydropyrazolo[4,3-c]pyridinyl, tetrahydropyrazolo[4,3-c]pyridinyl,pyrrolo[1,2-a]pyrazinyl, dihydropyrrolo[1,2-a]pyrazinyl,tetrahydropyrrolo[1,2-a]pyrazinyl, octahydropyrrolo[1,2-a]pyrazinyl,isoindolyl, indazolyl, indolinyl, isoindolinyl, quinolinyl,isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, andisochromanyl, wherein the bicyclic ring is unsubstituted or substitutedwith 1 or 2 substituents independently selected from: (a) halogenselected from —F, —Cl, and —Br, (b) methyl, (c) —CF₃, (d) methoxy, (e)—OCF₃, (f) —CN, (g) ═O, and (h) —OH; R^(t) is selected frompyrrolidinyl, pyrazolidinyl, imidazolinyl, piperidinyl, piperazinyl,pyrrolyl, pyridyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,pyrazinyl, pyrimidinyl, and pyradizinyl; any one of which isunsubstituted or substituted with 1 or 2 substituents independentlyselected from —F, —Cl, —Br, oxo, methyl, and methoxy; or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1, wherein each R^(k) is independently: (1) phenyl which isunsubstituted or substituted with from 1 to 2 substituents independentlyselected from: (a) halogen selected from —F, —Cl, and —Br, (b) methyl,(c) —CF₃, (d) methoxy, (e) —OCF₃, (f) phenyl, (g) —S—CH₃, (h) —CN, (i)—OH, (j) phenyloxy (k) —N(R^(a))₂, (l) —(CH₂)₁₋₃N(R^(a))₂, (m) —R^(t),(n) —(CH₂)₀₋₃C(═O)N(R^(a))₂, and (o) —(CH₂)₀₋₃C(═O)R_(a); (2) —C₃₋₆cycloalkyl; (3) a 5- or 6-membered heteroaromatic ring selected fromthienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolyl,isothiazolyl, pyrazinyl, pyirimidinyl, triazolyl, and tetrazolyl,wherein the heteroaromatic ring is unsubstituted or substituted onnitrogen or carbon with 1 or 2 substituents independently selected from:(a) halogen selected from —F, —Cl, and —Br, (b) methyl, (c) —CF₃, (d)methoxy, (e) —OCF₃, (f) —S—C₁₋₆ alkyl, (g) —CN, (h) —OH, (i) —N(R^(a))₂,(j) —C₁₋₆alkyl—N—(R^(a))₂, (k) —R^(t), (l) oxo, (m)—(CH₂)₀₋₃C(═O)N(R^(a))₂, and (n) —(CH₂)₀₋₃C(═O)R_(a); (4) a 5- or6-membered saturated heterocyclic ring selected from piperidinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl,oxazolidinyl, isooxazolidinyl, pyrrolidinyl, imidazolidinyl and,piperazinyl, wherein the heterocyclic ring is unsubstituted orsubstituted with 1 or 2 substituents independently selected from: (a)halogen selected from —F, —Cl, and —Br, (b) methyl, (c) —CF₃, (d)methoxy, (e) —OCF₃, (f) —CN, (g) ═O, (h) phenyl, (i) benzyl, (j)phenylethyl, (k) —OH, (l) —(CH₂)₀₋₃C(═O)N(R^(a))₂, (m)—(CH₂)₀₋₃C(═O)R^(a), (n) N(R^(a))—C(═O)R^(a), (o) N(R^(a))—C(═O)OR^(a),(p) (CH₂)₁₋₃N(R^(a))—C(═O)R^(a), (q) N(R^(a))₂, (r) (CH₂)₁₋₃N(R^(a))₂,(s) —(CH₂)₀₋₃C(═O)R^(t), (t) —R^(t), (u) —N(R^(a))R^(t), and (v)—(CH₂)₁₋₃R^(t); and (5) an 8- to 10-membered heterobicyclic ringselected from indolyl, imidazo[4,5-b]pyridinyl,dihydroimidazo[4,5-b]pyridinyl, pyrazolo[4,3-c]pyridinyl,dihydropyrazolo[4,3-c]pyridinyl, tetrahydropyrazolo[4,3-c]pyridinyl,pyrrolo[1,2-a]pyrazinyl, dihydropyrrolo[1,2-a]pyrazinyl,tetrahydropyrrolo[1,2-a]pyrazinyl, octahydropyrrolo[1,2-a]pyrazinyl,isoindolyl, indazolyl, indolinyl, isoindolinyl, quinolinyl,isoquinolinyl, quinoxalinyl, and quinazolinyl, wherein the bicyclic ringis unsubstituted or substituted with 1 or 2 substituents independentlyselected from: (a) halogen selected from —F, —Cl, and —Br, (b) methyl,(c) —CF₃, (d) methoxy, (e) —OCF₃, (f) —CN, (g) ═O, and (h) —OH; andR^(t) is selected from pyrrolidinyl, pyrazolidinyl, imidazolinyl,piperidinyl, piperazinyl, pyrrolyl, pyridyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, and pyradizinyl; any oneof which is unsubstituted or substituted with 1 or 2 substituentsindependently selected from —F, —Cl, —Br, oxo, methyl, and methoxy; or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 2, wherein A is (i) a monocyclic heterocycle selected from thegroup consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, pyridyl, oxazolyl, isooxazolyl, thiazolyl, pyrrolidinyl,piperidinyl, piperazinyl, thiazolidinyl, and morpholinyl; (ii) a fusedbicyclic heterocycle selected from the group consisting of indolyl,isoindolyl, phthalazinyl, benzimidazolyl, quinolinyl, isoquinolinyl,dihydroindolyl, dihydroisoindolyl, tetrahydroquinolyl,tetrahydroisoquinolyl, imidazo[1,2-a]pyrimidinyl,2,3-dihydroimidazo[2,1-b][1,3]thiazolyl, benzazepinyl,dihydrobenazepinyl, benzodiazepinyl, dihydrobenzodiazepinyl,benzothiazolyl and tetrahydrobenzodiazepinyl; or (iii) a fused tricyclicheterocycle selected from the group consisting of phenothiazinyl,beta-carbolinyl, and tetrahydro-beta-carbolinyl; or a pharmaceuticallyacceptable salt thereof.
 4. The compound according to claim 3, wherein Ais selected from the group consisting of indolyl, phenothiazinyl,benzimidazolyl, phthalazinyl, and dihydroimidazothiazolyl; or apharmaceutically acceptable salt thereof.
 5. The compound according toclaim 3, wherein A is indolyl; or a pharmaceutically acceptable saltthereof.
 6. A compound according to claim 1, which is a compoundselected from the group consisting of2-({[(8-hydroxy-1,6-naphthyridin-7-yl)carbonyl]amino}methyl)-1H-benzimidazole;8-hydroxy-N-[2-(1H-indol-3-yl)ethyl]-1,6-naphthyridine-7-carboxamide;N-{2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethyl}-8-hydroxy-1,6-naphthyridine-7-carboxamide;8-hydroxy-N-[(2-oxo-2,3-dihydro-1H-indol-3-yl)methyl]-1,6-naphthyridine-7-carboxamide;8-hydroxy-N-[2-(10H-phenothiazin-10-yl)ethyl]-1,6-naphthyridine-7-carboxamide;8-hydroxy-N-[2-(2-methyl-1-phenyl-1H-indol-3-yl)ethyl]-1,6-naphthyridine-7-carboxamide;8-hydroxy-N-(1H-indol-6-ylmethyl)-1,6-naphthyridine-7-carboxamide;8-hydroxy-N-(1H-indol-2-ylmethyl)-1,6-naphthyridine-7-carboxamide;8-hydroxy-N-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]-1,6-naphthyridine-7-carboxamide;tert-butyl3-({[(8-hydroxy-1,6-naphthyridin-7-yl)carbonyl]amino}methyl)-1H-indole-1-carboxylate;8-hydroxy-N-(1H-indol-3-ylmethyl)-1,6-naphthyridine-7-carboxamide;6-({[(8-hydroxy-1,6-naphthyridin-7-yl)carbonyl]amino}methyl)-2,3-dihydroimidazo[2,1-b][1,3]thiazole;8-hydroxy-N-(4-pyridinylmethyl)[1,6]naphthyridine-7-carboxamide;8-hydroxy-N-(2-pyridinylmethyl)[1,6]naphthyridine-7-carboxamide; andpharmaceutically acceptable salts thereof.
 7. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.
 8. A method for treatinginfection by HIV or treating or delaying the onset of AIDS in a subjectin need thereof which comprises administering to the subject atherapeutically effective amount of the compound according to claim 1,or a pharmaceutically acceptable salt thereof.
 9. A method for treatinginfection by HIV or for treating or delaying the onset of AIDS in asubject in need thereof which comprises administering to the subject atherapeutically effective amount of the composition according to claim7.
 10. A pharmaceutical composition which comprises the product preparedby combining an effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.